Progress in lymphedema.

A century ago, the first description of secondary lymphedema resulting from mastectomy was published in the medical literature. For most of the remaining twentieth century, evidence about cancer treatment related lymphedema grew slowly, and mostly through clinicians who wished to understand its causes, natural-history, and post-treatment risks, as well as from clinicians involved with its treatment. In the late 1990s, there was growing recognition that there were large gaps in our understanding of predisposing and post-treatment risks of onset, the near and long-term prevalence of lymphedema, and how to educate patients. Moreover, there was no consensus on best practices for treating lymphedema, and how to ensure the quality of treatment. In 1998, with support from the Longaberger Company®, the American Cancer Society began a long-standing commitment to address enduring challenges associated with lymphedema. This commitment began with a landmark international workshop on lymphedema that was held in New York City in February 1998, millions of dollars in research funding, support to establish the Lymphology Association of North America (LANA), a second workshop convened in February 2011 on the prospective surveillance model for rehabilitation for women with breast cancer, and most recently, the 2023 Lymphedema Summit: Forward momentum; Future Steps in Lymphedema Management, co-sponsored with the LANA, Washington University School of Medicine in St. Louis, and the Stryker Corporation. This editorial introduces the papers and expert consensus statements from that Summit.

Multi-omics characterization of lymphedema-induced adipose tissue resulting from breast cancer-related surgery.

Secondary lymphedema (LE) following breast cancer-related surgery is a life-long complication, which currently has no cure. LE induces significant regional adipose tissue deposition, requiring liposuction as a treatment. Here, we aimed to elucidate the transcriptional, metabolomic, and lipidomic signature of the adipose tissue developed due to the surgery-induced LE in short- and long-term LE patients and compared the transcriptomic landscape of LE adipose tissue to the obesity-induced adipose tissue. Adipose tissue biopsies were obtained from breast cancer-operated females with LE from the affected and non-affected arms (n = 20 patients). To decipher the molecular properties of the LE adipose tissue, we performed RNA sequencing, metabolomics, and lipidomics combined with bioinformatics analyses. Differential gene expression data from a cohort of lean and obese patients without LE was used for comparisons. Integrative analysis of functional genomics revealed that inflammatory response, cell chemotaxis, and angiogenesis were upregulated biological processes in the LE arm, indicating a sustained inflammation in the edematous adipose tissue; whereas, epidermal differentiation, cell-cell junction organization, water homeostasis, and neurogenesis were downregulated in the LE arm. Surprisingly, only a few genes were found to be the same in the LE-induced and the obesity-induced adipose tissue expansion, indicating a different type of adipose tissue development in these two conditions. In metabolomics analysis, we found reduced levels of a branched-chain amino acid valine in the LE arm and downregulation of the mRNA levels of its transporter SLC6A15. Lipidomics analyses did not show any significant differences between the LE and non-LE arms, suggesting that other factors affect the lipid composition of the adipose tissue more than the LE in these patients. Our results provide a detailed molecular characterization of adipose tissue in secondary LE after breast cancer-related surgery. We also show distinct differences in transcriptomic signatures between LE-induced adipose tissue and obesity-induced adipose tissue, but only minor differences in metabolome and lipidome between the LE and the non-LE arm.

Consensus statement on non-cancer-related risk factors for development of secondary lymphedema.

Non-cancer-related risk factors for secondary lymphedema were defined across four categories: co-morbidity, social determinants of health, behavioral factors, and environmental effectors. Based on rapid reviews of the literature and presentations at the ACS/LANA Lymphedema Summit, this working group categorized these risk factors according to the strength of evidence. Consensus agreement on level of evidence was achieved through one face-to-face working session and three follow-up virtual meetings. Findings elucidate strong evidence for co-morbidities, such as cardio/metabolic and vascular factors contributing to the risk for lymphedema. Evidence is low-to-moderate for social and behavioral factors and is lacking for environmental factors. Panel recommendations suggest a tailored approach to prospective surveillance when monitoring for secondary lymphedema that includes social determinants of health considering the growing awareness and evidence of these factors' influence on cancer and cancer-related morbidity.

The influence of non-cancer-related risk factors on the development of cancer-related lymphedema: a rapid review.

Extensive research supports an evidence-base for cancer treatment-related risk factors, including extent of lymph node dissection and use of radiotherapy, as contributing to secondary lymphedema. Additionally, comorbidities, such as higher body mass index, and vascular-related conditions are identified to further augment risk. While social determinants of health (SDOH) and socioeconomic factors are widely regarded as influencing an individual's healthcare outcomes, including cancer risk and survival, these factors have not been explored as risk factors for developing secondary lymphedema. A rapid literature review explored the current evidence for SDOH as risk factors for lymphedema. Studies that were published over the last 10 years and that specifically analyzed social factors as variables associated with lymphedema were included. Studies that only characterized the social determinants of the study population were not included. Forty-nine studies were identified through a rapid literature review, and 13 studies that expressly analyzed social determinants as risk factors for secondary lymphedema were reviewed and extracted. All studies were conducted in patients with breast cancer-related lymphedema. Social risk factors included race, educational level, insurance type, and income level. These are consistent with the socioeconomic inequalities related to cancer survival. SDOH may influence the risk of developing cancer treatment-related health conditions like secondary lymphedema. Research trials studying cancer treatment-related conditions should collect consistent and robust data across social, behavioral, environmental, and economic domains and should analyze these variables to understand their contribution to study endpoints. Risk prediction modeling could be a future pathway to better incorporate social determinants, along with medical and co-morbidity data, to holistically understand lymphedema risk.

Incidence of lymphedema related to various cancers.

Cancer-related lymphedema (CRL) lacks internationally accepted definition and diagnostic criteria. The accurate incidence of CRL is therefore a challenge and the condition is likely underreported. Patients treated for cancer can develop CRL as a result of surgery, chemotherapy, and/or radiotherapy, which can lead to considerable psychosocial and physical morbidity, and decreased quality of life. Determining CRL incidence is crucial to inform care access and resource allocation, to best support patients affected by this lifelong condition. This review aimed to provide the latest CRL incidence estimates. Using four core databases (MEDLINE, Embase, Web of Science Core Collection, Cochrane Library), a literature search was performed to capture publications dated between 2015 and 2023. A total of 48 articles (33 prospective studies, 15 systematic reviews) met inclusion criteria, providing a sample size of 234,079 cancer patients. Findings revealed CRL incidence across cancer types varied, reported 2-74% in breast, 8-45% in gynecological and urological, 71-90% in head and neck and 2-29% in melanoma cancers. CRL incidence varied between 3 and 21% in preventative lymphedema surgery patients. Projected increases in cancer incidence and improved survival rates are expected to further escalate CRL incidence. Healthcare systems and professionals alike must therefore prepare to meet the growing needs of CRL patients.

Larger recipient vein caliber during lymphatic microsurgical preventive healing approach (LYMPHA) is associated with lower lymphedema rates.

BACKGROUND: The lymphatic microsurgical preventive healing approach reduces the risk of lymphedema after axillary lymph node dissection. We identified surgical factors of Lymphatic Microsurgical Preventive Healing Approach (LYMPHA) that influence lymphedema rates focusing on the vein caliber used. METHODS: A single-institution retrospective cohort study included breast cancer patients undergoing axillary lymph node dissection and LYMPHA (April 2021-November 2022) with a follow-up of at least 1 year. Lymphedema was defined as an increase of ≥10 units in the lymphedema index (measured using bioimpedance spectroscopy) from baseline. The primary outcome was the correlation between the lymphedema index of patients with a vein caliber of ≤2 mm vs > 2 mm. RESULTS: Forty-eight patients with documented vein caliber were analyzed. The median baseline lymphedema index in patients with a vein caliber ≤2 mm was 2 (SD 3.04) and 2.2 (SD 2.03) for vein caliber >2 mm. (P = .57). After 1-year follow-up, the L-dex was 6.20 (SD 7.48) for vein caliber ≤2 mm and 1.60 (SD 5.85) for vein caliber >2 mm (P = .02). The L-dex difference from baseline was higher for vein caliber ≤2 mm compared to >2 mm (2.9 vs 0.10, P = .02). Larger vein caliber was associated with a lower L-dex at 3 months (P = .04) and a lesser difference from the baseline after 1 year (P = .03). This was maintained on univariate analysis and multivariate analysis controlling for radiation, chemotherapy, and number of lymph nodes excised. CONCLUSION: Vein caliber >2 mm during LYMPHA axillary lymph node dissection is associated with a lower postoperative lymphedema index. These results can be enhanced by a multi-institutional study to improve standardization of this technique.

New insights in breast cancer-related lymphedema.

Upper limb lymphedema after breast cancer treatment including axillary dissection occurs in almost 20% of women. Its treatment consists of complete decongestive physiotherapy based on low-stretch bandage to reduce volume, followed by elastic compression to maintain it. In this article, we will detail recent data on lymphedema risk factors with possible genetic predisposition, prevention (surgical, compression), manual lymphatic drainage, physical activity, weight, advice, and treatments including gene therapy.

Characteristics of lymphoedema, in particular midline lymphoedema, after treatment for prostate cancer: a retrospective study.

BACKGROUND: Patients undergoing treatment for prostate cancer may develop lymphoedema of the midline region. This has a substantial impact on a patient's quality of life and its diagnosis is often delayed or missed. Therefore, the purpose of this study is to compare the characteristics of patients with leg and midline lymphoedema to patients with only leg lymphoedema. METHODS: We retrospectively collected patient-, cancer-, lymphoedema- and lymphoedema treatment-related data of 109 men with lymphoedema after treatment for prostate cancer. First, 42 characteristics were compared between both groups. Second, factors predicting presence of midline lymphoedema were explored by multivariable analyses. RESULTS: The mean age of the patients with lymphoedema was 68 ( ±7) years and mean BMI is 28 (±4) kg/m2. Median duration of lymphoedema before the first consultation was 27 (9;55) months. Based on univariable analyses, patients with leg and midline lymphoedema had more frequently upper leg lymphoedema (89% (31/35) vs. 69% (51/74), p = 0.026), skin fibrosis (34% (12/35) vs. 16% (12/74), p = 0.034) and lymphatic reconstructive surgery (9% (3/35) vs. 0% (0/71), p = 0.020) than patients with only leg lymphoedema. Additionally, patients with leg and midline lymphoedema reported less frequently lower leg lymphoedema (77% (27/35) vs. 95% (70/74), p = 0.007). Based on the multivariable analysis, not having lower leg lymphoedema, skin fibrosis, performing self-bandaging and self-manual lymphatic drainage appear to be predictors for having midline lymphoedema. CONCLUSIONS: If patients with lymphoedema after prostate cancer do not have lower leg lymphoedema, have skin fibrosis, perform self-bandaging or self-manual lymphatic drainage, they possibly have midline lymphoedema.

Breast cancer-related lymphedema: A critical review on recent progress.

Lymphedema is a chronic and debilitating condition characterized by an abnormal buildup of protein-rich fluid in the interstitial tissue, leading to the development of edema and tissue structural alterations. Breast cancer-related lymphedema (BCRL) remains a significant healthcare burden because it can develop within days and up to 11-years after the surgery. Specifically, axillary lymph node dissection leads to 30-50 % upper limb lymphedema, which involves the accumulation of protein-rich fluid. In this article, we provide a comprehensive/critical overview of post-mastectomy lymphedema, focusing on key aspects as diagnosis, prevention, and treatment methods. Beginning with clinical condition, the article explores the pathophysiology and risk factors associated with post-mastectomy lymphedema. It further delves into various diagnostic modalities available, highlighting the importance of early detection for optimal management of BCRL. We also examine preventive strategies, emphasizing the role of patient education, lifestyle modifications, and proactive measures in reducing the risk of lymphedema development. In terms of treatment, the article covers a wide array of interventions ranging from conservative approaches like manual lymphatic drainage and compression therapy to surgical techniques such as lymph node transfer and lymphaticovenular anastomosis. Thus, through a comprehensive synthesis of current evidence and clinical practices updates, the review aims to guide healthcare professionals in delivering preventive and effective care while improving outcomes for individuals affected by post-mastectomy lymphedema.

The Effects of Daily-Living Risks on Breast Cancer-Related Lymphedema.

BACKGROUND: Conventional advice to reduce the risk of breast cancer-related lymphedema (BCLE) suggests avoidance of daily-living risks, and limited research has investigated these risks. OBJECTIVE: This study aimed to examine the occurrence, patterns, and effects of daily-living risks on BCLE. METHODS: A cross-sectional design was used to collect data from 567 patients at a metropolitan cancer center in the United States. The Lymphedema Risk-Reduction Behavior Checklist was used to assess the occurrence of 11 daily-living risks. Descriptive, regression, and factor analyses were performed. RESULTS: Significant odds of BCLE were associated with infection (odds ratio [OR] 2.58, 95% confidence interval [CI] 1.95-3.42), cuts/scratches (OR 2.65, 95% CI 1.97-3.56), sunburn (OR 1.89, 95% CI 1.39-3.56), oil splash or steam burns (OR 2.08, 95% CI 1.53-3.83), and insect bites (OR 1.59, 95% CI 1.18-2.13). The daily-living risks were clustered into factors related to skin trauma and carrying objects. Skin trauma risk was significantly associated with BCLE (B = 0.539, z = 3.926, OR 1.714, 95% CI 1.312-2.250; p < 0.001). Having three, four, or five skin trauma risks significantly increased the odds of BCLE to 4.31, 5.14, and 6.94 times, respectively. The risk of carrying objects had no significant or incremental effects on BCLE. CONCLUSION: Complete avoidance of daily-living risks is challenging given 52.73% of patients incurred more than five daily-living risks. Our study findings underscore the importance of 'what to do' strategies to minimize infection and skin trauma.

Analysis of Different Lymphedema Assessment Tools in Women with Breast Cancer After Mastectomy.

Background: Lymphedema is a common complication after mastectomy in women with breast cancer. Several methods have been described to assess and diagnose lymphedema, one of the most studied being the perimeter and ultrasonography. However, the reliability of these methods and the correlation between them are still controversial. The aim of this study was to analyze the reliability of cytometry and ultrasound imaging in the assessment of lymphedema after mastectomy in women with breast cancer and to study the correlation between them. Methods and Results: A cross-sectional study was conducted in 29 women with mastectomy after breast cancer. Lymphedema in the arm was measured both with cytometry and ultrasonography. Reliability was calculated with intraclass correlation coefficient. The correlation between the two methods was carried out with the Pearson correlation coefficient. Both cytometry (M1: α = 0.999, ICC = 0.996; M2: = α = 0.998, ICC = 0.994) and ultrasonography (M1: α = 0.992, ICC = 0.976; M2: = α = 0.991, ICC = 0.973) are reliable methods to assess lymphedema in the arm. No significant correlation was found between them (p > 0.05). Conclusions: Cytometry and ultrasonography appear to be adequate for the measurement of edema in women with breast cancer after mastectomy. However, for an accurate measurement of lymphedema, these measurements should not be used interchangeably.

Evidence for the clinical effectiveness of decongestive lymphoedema treatment for breast cancer-related arm lymphoedema, a systematic review.

PURPOSE: Early treatment is advised for breast cancer-related arm lymphoedema (BCRL), a common sequelae of breast cancer treatment. Expert guidance recommends two-phase decongestive lymphoedema treatment (DLT), although evidence is lacking for current treatment protocols and UK women are routinely offered self-treatment with hosiery. This systematic review considered evidence regarding treatment of early BCRL, that is, within 12 months of developing BCRL. METHODS: A systematic review of evidence for clinical effectiveness of DLT for women with less than 12-month BCRL duration (early BCRL) was undertaken using the Joanna Briggs Institute (JBI) method. Studies included women with < 12-month or mean < 9-month BCRL duration; some studies reported only one eligible group. The original search was conducted in 2016 and updated in 2018 and 2022. Methodological quality of identified studies was assessed using JBI critical appraisal instruments. Outcomes of interest were extracted with eligible results displayed in narrative and tabular format. Strength of evidence was rated using the GRADE system. RESULTS: Seven trials and three descriptive studies provided weak evidence (grade B) for effectiveness of DLT for early BCRL. Heterogeneous protocols limited comparison of findings. There was no evidence for the most effective treatment or treatment combination or optimal frequency or duration of treatment. CONCLUSION: There is no evidence to justify change in current lymphoedema treatment, whether self-treatment with hosiery (UK) or two-phase DLT (other countries). Further research for the early BCRL population is required. IMPLICATIONS FOR CANCER SURVIVORS: Women with early BCRL require early and effective treatment although this updated review shows there is still no evidence for what that treatment should be.

LYMPH-Q translation, cultural adaptation and validation in Italian language: A prospective PROMs-based study on breast cancer-related arm lymphedema for patients' education.

BACKGROUND: Upper Extremity Lymphedema following oncological breast surgery affects not only the patient's physique, but also the patient's psychological sphere. One of the best known PROMs-based questionnaires for investigating the condition is the LYMPH-Q. The study aimed to perform the Italian translation and cultural adaptation of the LYMPH-Q and to assess if, independently from disease evolution, arm sleeve improves QoL in these patients. MATERIALS AND METHODS: Translation included 4 steps: Forward translation, Back translation, Back translation review and Patient interviews. The questionnaire was administered to 50 female patients older than 18 years of age with UEL who received a prescription for daily use of a compression sheath. A second administration took place 30 days after. Forty-four patients completed the study (Group 1: 26 patients with indication to use compression sleeve who wore it; Group 2:18 patients who despite the prescription did not want to wear it. A descriptive statistical analysis was performed with Prism 9 software. RESULTS: T-tests showed statistical significance for changes in "Symptoms," "Function," "Appearance" and "Psychological" scales. There were no statistically significant changes for "Information scale" in Group 1 and for all scales in Group 2. CONCLUSION: Data from this observational study show that HR-QOL analyzed from the patients' perspective also tends to improve in terms of symptoms, function, appearance, and psychological sphere in patients with BCRL when using a compression sheath. The Lymph-Q has proven to be a valuable ally of the physician attempting to improve treatment approaches for BCRL based not only on scientific evidence but also on PROMs.

Prevention and Treatment of Lymphedema in Breast Cancer.

Breast cancer related lymphedema (BCRL) affects many breast cancer survivors and drastically affects their quality of life. There are several surveillance methods for BCRL that are critical at early detection. Prevention of BCRL involves knowledge of alternatives to aggressive axillary surgery, avoidance of axillary surgery, and de-escalation of axillary surgery. There are also techniques to better delineate the anatomy in the axilla to avoid taking nodes that drain the upper extremity. A multidisciplinary approach with medical oncology and radiation oncology can also help avoid unnecessary surgery or radiation that can together strongly increase the risk of BCRL.

Lymphedema self-management mobile application with nurse support for post breast cancer surgery survivors: description of the design process and prototype evaluation.

BACKGROUND: Self-management is the key to control breast cancer related lymphedema (BCRL). This study aimed to develop a mobile application with nurse support for lymphedema self-management and evaluate its usability from the patients' points of view. METHODS: This applied developmental study was conducted on 87 women in a lymphedema clinic, Shiraz, Iran, May-November 2023. The study included three phases: development, distribution of the application and usability evaluation. In the development phase, the researchers developed application using the Java programming language. In distribution phase, the application was installed on the participants' phones. For usability evaluation, 87 patients completed the user satisfaction questionnaire after three months access to the application. Data was analyzed using descriptive and analytical statistics using SPSS software 22. P-value less than 0.05 was considered significant. RESULTS: We designed a self-management application specific to BCRL that included ten unique modules mainly related to patient education, interaction with peers and nurse, self-management support, and settings. The application mean usability score was 7.72 ± 1.08. The usability dimensions of "screen" (8.06 ± 1.02) and "terminology and systems information" (7.29 ± 1.62) received the highest and lowest mean scores, respectively. CONCLUSION: The application has new features to meet more patients' needs compared to what other existing lymphedema self-management applications already have addressed. The findings showed that the participants rated the application usability at the "good" level that is similar to some previous studies. Considering the unique nature of the application and its favorable usability, we recommend its use for BCRL self-management.

Chronic Wound Caused by Lymphorrhea after Skin Abscess Drainage on Lower Extremity: A Case Report.

ABSTRACT: Surgical operations such as lymph node dissection may inadvertently damage the lymphatic system and lead to lymphorrhea. Excessive lymphatic exudation can cause a chronic wound. However, for surgery that does not involve the lymphatic system, lymphorrhea is a rare postoperative complication. This case report describes a 38-year-old patient who presented with lymphatic cutaneous leakage after incision and drainage of a skin abscess on the lower extremity. Persistent lymphorrhea increased the amount of wound exudation, which affected wound healing. After treatment of the lymphorrhea, the lower extremity wound healed completely within 4 weeks and did not result in lymphedema. Ligation of lymphatic vessels is a simple and easily performed treatment method for lymphatic leakage.

Lymphedema in Turner syndrome: correlations with phenotype and karyotype.

OBJECTIVES: Lymphedema (LD) in Turner syndrome (TS) is a commonly reported comorbidity, though its associations with karyotype and other comorbidities are poorly understood. Characteristics of patients with TS and LD, including correlation with phenotype and karyotype, are described. METHODS: Medical records of patients with TS seen in two pediatric institutions from 2002 to 2020 were retrospectively reviewed. Demographic data (age, presentation onset, clinical features, genetics, LD presence, investigations, treatments) were collected. RESULTS: 393 girls with TS with mean age of 12.5 years (SD: 5.7) were identified. LD was noted in 37 % of patients (n=146). Among the 112 patients with TS and documentation of onset of LD, LD was noted within the first year of life in 78.6 % (n=88). 67.6 % (n=96) of total patients with TS and LD had non-mosaic 45, X karyotype. Frequency of webbed neck was significantly greater in girls with TS and LD compared with girls without LD (58 vs. 7 %, p<0.001). Congenital heart anomalies, hypertension, and renal anomalies were also more common in girls with LD. Nail abnormalities with presence of hypoplastic or dysplastic nails were significantly associated with LD (OR: 6.784, 95 % CI 4.235-11.046). The number of girls reporting presence of LD decreased with age. CONCLUSIONS: LD in TS often occurs within the first year of life, is less prevalent in older children and adolescents, and is significantly associated with 45, X karyotype, presence of webbed neck, nail changes, congenital heart anomalies, and renal anomalies.