• Vol. 53 No. 2, 80–89
  • 28 February 2024

Defining breast cancer-related lymphedema (BCRL) prevalence and risk factors: A pragmatic approach to lymphedema surveillance

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ABSTRACT

Introduction: We presented the key findings from Singapore’s Changi General Hospital Breast Centre’s lymphedema surveillance strategy that used patients’ reported symptoms, standard arm circumference measurements and clinical assessment in the diagnosis of breast cancer-related lymphedema (BCRL). Our secondary aim was to highlight and discuss important elements of a surveillance strategy that can be implemented to track this outcome measure of breast cancer treatment for future research.

Method: We conducted a cross-sectional study of 511 breast cancer patients to assess the prevalence of BCRL and its associated risk factors. We defined BCRL prevalence rates based on patients’ self-reporting, objective arm circumference measurements and clinical diagnosis based on International Society of Lymphology (ISL) staging.

Results: The median follow-up of patients was 88.8 months. The cumulative prevalence rate in the cohort was 30.9%. The cohort of BCRL patients were older (58.4 versus [vs] 54.9 years), had higher mean Body Mass Index (27.7 vs 25.2), higher proportion of mastectomy (77% vs 64.3%), axillary clearance, less likely breast reconstruction, higher-grade tumour, more lymph nodes excised, more advanced nodal disease, and had undergone adjuvant chemotherapy. However, clinically apparent BCRL was only 6.5% (33 out of 511 patients). The proportion of clinically significant BCRL in patients undergoing sentinel lymph node biopsy (SLNB) or axillary sampling was 1.7% compared to 9.9% in patients who had undergone axillary clearance. Majority of the BCRL were subclinical or mild in severity.

Conclusion: Our study showed that our rates of BCRL were comparable to international rates and highlighted similar patient profiles who were at risk of developing the disease. Having a comprehensive lymphedema surveillance strategy is paramount in paving the way for future studies.


CLINICAL IMPACT

What is New

  • This study is the first to highlight prevalence and risk factors of developing breast cancer-related lymphedema in Singapore.
  • Findings underscore the importance of a comprehensive lymphedema surveillance strategy in any breast unit.

Clinical Implications

  • The study highlights the effectiveness of simple assessment tools such as patient questionnaires, regular arm circumference measurement before and after treatment, clinical assessment matrix for diagnosis of BCRL and timely intervention.
  • This data can potentially inform guidelines for lymphedema surveillance strategy in Singapore.


Breast cancer-related lymphedema (BCRL) is a chronic progressive pathological condition of the lymphatic system that can lead to significant impact on the quality of life after breast cancer treatment.1 It is characterised by swelling and accumulation of protein-rich fluid in body tissues, leading to pain, tightness, skin changes such as fibrosis/thickening or recurrent infections, impaired mobility, and function of the affected arms. BCRL has an insidious onset and can occur even without precipitating events, years after treatment. Systematic reviews have shown that interventions tend to be more effective in the initial stages of lymphedema, before permanent changes such as fibrosis set in.2,3 However, due to a lack of standardised diagnostic criteria, BCRL is still notoriously difficult to detect in its early stages.4 Hence, it is important to have a lymphedema surveillance strategy that starts as early as from the time of cancer diagnosis and persists beyond treatment.

The incidence of BCRL has been reported to range from 0% to 94% of the breast cancer survivors.3-12 This wide variation in incidence is largely owing to a difference in study designs, diagnostic methods, a lack in consistency of objective measures of BCRL, and varying timing of measurements. The lack of local data on the prevalence of BCRL in Singapore makes it difficult to quantify the extent of the morbidity or to study the effectiveness of interventions aimed at curtailing them.

In this paper, we present the key features of Singapore’s Changi General Hospital Breast Centre’s approach to lymphedema surveillance that has been using standard arm circumference measurements as an adjunct objective reading to aid in the diagnosis of BCRL. Finally, we conducted a cross-sectional study of our centre’s breast cancer survivors to examine the performance of a set of predefined subjective and objective assessment tools, to assess for the prevalence of BCRL along with its associated risk factors. Our aim is to highlight and discuss the importance of a surveillance strategy that is evidence-based and can be implemented readily to track the magnitude and severity of BCRL as an outcome measure of breast cancer treatment.

METHOD

Lymphedema surveillance programme

A comprehensive lymphedema surveillance programme, started in 2019 at Changi General Hospital Breast Centre, included patient education on the condition, advice on arm care, and range-of-motion exercises (Fig. 1). These were taught to the patients prior to the initiation of any treatment and reinforced at each touch point by their respective treating clinicians and nurses. Baseline arm circumference measurements were also obtained by both trained nurses and clinicians.

Fig. 1. Our surveillance strategy for breast cancer related lymphedema (BCRL).

Criteria for BCRL diagnosis

  • Arm circumference was taken at 10 cm below and above the olecranon and a difference ≥2 cm from the contralateral arm or from baseline was taken to be indicative of BCRL.
  • Patients’ self-reported diagnosis of BCRL and/or subjective complaints of persistent arm swelling for more than 1 month were considered to be indicative of BCRL.
  • All clinicians assessed for the presence of BCRL based on patient symptoms and arm circumference measurements. If present, clinicians graded the severity of lymphedema according to International Society of Lymphology (ISL) (Fig. 2).

Fig. 2. Severity of BCRL diagnosed according to International Society of Lymphology (ISL).

Patients who were assessed to have risk factors and fulfilled any of the diagnostic criteria of BCRL or presence of triggers were offered referrals to our specialised lymphedema therapist for further evaluation and appropriate interventions.

A total of 511 patients who were treated and on follow-up for breast cancer surveillance in Changi General Hospital Breast Centre were recruited by convenient sampling between March and September 2021 for the cross-sectional study. The prevalence of lymphedema using patients’ subjective complaints or self-reporting method, objective arm circumference measurements and clinicians’ independent assessments were analysed for agreement.  Patients who had metastatic breast cancer, bilateral breast cancer, disease recurrence or declined curative surgery were excluded. Based on the cumulative diagnosis of BCRL, we analysed the clinical risk factors associated.

This study was approved by SingHealth Centralised Institutional Review Board 2021/2068 to be conducted in Changi General Hospital.

Statistical analysis

Percent agreement and Cohen’s kappa coefficient were used to analyse inter-rater variability between the assessment tools. Categorical variables were analysed using the chi-square or Fisher’s Exact test, and continuous variables were analysed using the Student’s t-test. A P value of <0.05 was considered statistically significant. Statistical analysis was performed in March 2022 using Stata SE version 17 (StataCorp, College Station, TX, US).

RESULTS

Patients’ clinical demographic and risk factors associated with BCRL

The median follow-up of patients was 88.8 months (Table 1). The cumulative prevalence rate in the cohort was 30.9% when using any of the diagnostic criteria. This cohort of BCRL patients had a higher mean age (58.4 vs 54.9 years), higher mean BMI (27.7 vs 25.2), higher proportion of whom have undergone mastectomy (77% vs 64.3%), axillary clearance, less likely breast reconstruction, higher-grade tumour, more lymph nodes excised, more advanced nodal disease, and had undergone adjuvant chemotherapy.

Table 1. Demographic of all patients cumulatively diagnosed with BCRL by self-reported symptoms, arm circumference measurements, or clinician assessment.

Prevalence by various assessment tools and inter-rater reliability

Based on our study, the prevalence of BCRL diagnosed by arm circumference measurements was the highest at 18.9% (89 out of 511), whereas clinicians’ assessment was the lowest at 6.5% (33 out of 511). When using any of the diagnostic criteria, the cumulative prevalence was 30.1% (154) (Table 2). Although there was a high percent agreement rate of >80% between self-reported symptoms/arm circumference and clinical diagnosis of BCRL, the Cohen’s kappa agreement for inter-rater reliability was only fair (0.19–0.31, P<0.001).

Table 2. Prevalence by assessment tools and inter-rater reliability.

Clinically significant BCRL determined by attending clinician

The overall clinical BCRL diagnosed by clinician was only 6.5% (33 out of 511). Of note, the observed proportion of clinical BCRL in patients undergoing SLNB/axillary sampling was 1.7% compared to 9.9% in patients who undergone axillary clearance (Table 3). Majority of the BCRL severity were subclinical or mild (ISL stages 0–1), while only 7 out of 33 were considered moderate (ISL stage 2). None were severe (ISL stage 3) nor required radical resection with or without lymphatic reconstruction (Fig. 2). Only 33% (11 out of 33) of patients with BCRL had active therapist review. These patients were given reinforcement on skin care advice and offered compression sleeve prescription (ISL stages 0–1), or received manual lymphatic drainage, and compression bandage (ISL stage 2). Although suitable cases were discussed for lymphatic restoring procedures, there was little uptake. The rest either defaulted due to poor compliance or were discharged to self-therapy.

Table 3. Demographic of patients with clinical BCRL diagnosed by physician.

DISCUSSION

Local prevalence rates are comparable to internationally observed data despite higher rates of mastectomy and axillary dissection

This study highlighted the prevalence rates of BCRL in a single tertiary breast unit with an established lymphedema surveillance strategy. Comparable to other studies in our literature review, the prevalence of BCRL was estimated to be less than a third of the cohort (6.5–30.8%).3-12 This was lower than expected despite the cohort having a higher rate of mastectomy and axillary clearance performed (>50%). These risk factors were hypothesised to contribute to the rates of BCRL due to their extent of surgical disruption of the draining lymphatics.10,12 The proportion of breast surgery performed was at least reflective of the practice in Singapore and other Southeast Asian countries in the last decade, whereby rates of mastectomy with or without axillary dissection may be higher due to reasons such as breast cancer being diagnosed at a more advanced stage, and psychosocial reasons such as fear of cancer relapse, perception that health is more important than breast retention, possibility of involved margins.13-17

However, breast surgery has seen a trend of de-escalating axillary treatment aimed at producing equivalent survival outcomes and omitting previously routine surgical therapies such as axillary lymph node dissection or radiation in select group.18-22 This is expected to further improve arm morbidities outcome assessment such as BCRL and shoulder dysfunctions. The rates of BCRL will continue to form an important part of performance indicators of any contemporary breast unit. This study is therefore important to set a benchmark for prevalence rates not only as a cumulative rate, but identify the relative risk of BCRL associated with various treatment and risk factors.

Differentiating clinical BCRL from other causes

The result demonstrated variation in the estimation of prevalence of BCRL depending on the type of assessment tools used. Patient-reported BCRL was higher compared to clinician-diagnosed BCRL. However, the latter also represented the most clinically significant BCRL requiring interventions that were not due to other medical causes. Clinical surveillance post-cancer treatment was aimed at excluding disease recurrences, and other breast cancer treatment-related morbidities that could also impair functional outcomes and quality of life. This required clinicians to take into account patients’ underlying risk factors and potential competing diagnosis. Patient-subjective complaints of shoulder dysfunction or altered limb sensation may be caused by common conditions such as frozen shoulder or adhesive capsulitis, carpal tunnel syndrome, tenosynovitis.23,24 Other contributing conditions such as chemotherapy-induced peripheral neuropathy (CIPN), aromatase inhibitor-induced musculoskeletal syndrome (AIMS), radiation-induced fibrosis, axillary cording syndrome may often co-exist (Fig. 1).25-30 Similarly, arm swelling could be due to other causes such as fluid overload, venous disorders or disease recurrence. These should be excluded with the relevant tests. Rates of BCRL by patients’ reporting may therefore be an overestimation due to any of these confounding factors.30,31

These factors ultimately explained the relatively low Cohen’s kappa coefficient because the patients’ signs and symptoms can be wrongly alluded to BCRL. This highlighted a significant difference and lack in objectivity across the assessment tools. However, given the limitations of the available measurement tools, the authors proposed to include all of the findings collectively from directed questioning of patient symptoms, objective measurement of arm circumference and finally, an assessment matrix to consider various confounding diagnosis in the lymphedema surveillance strategy.31

Focus on evidence-based recommendations

The clinical risk factors associated with BCRL identified in our current study corroborated with those in literature review.30 These risk factors included elevated BMI, higher tumour and nodal pathological stage, presence of axillary clearance and chemotherapy. This at-risk group may benefit from a more intensive lymphedema surveillance strategy and recommendation. Risk factors directly related to disease and treatment factors may be unavoidable, but certain modifiable targets such as obesity or weight gain after treatment, and minimising infections or injury to the at-risk limb can be emphasised during patient education.30-32 Our institutional practice was to address clinical risk factors in accordance with established lymphedema clinical guidelines and avoid precautionary advice or primary prevention strategies that may engender unnecessary fear, restrictions or confusion from the inconsistency messaging. For example, avoiding of air travel, avoiding extreme of temperatures, vigorous exercise or the restrictions of use of the at-risk limb for blood pressure taking, venipuncture and/or peripheral intravascular line placement—to date, these have largely not been shown to be conclusively associated with development of lymphedema and their level of supporting evidence remained debatable.32-38

Strengths and limitations

The strength of the findings was derived from a comprehensive lymphedema surveillance strategy that was practised consistently by all participating clinicians after reviewing the latest available literature.30 The merits of this surveillance strategy included its ease of implementation as it did not rely on sophisticated tools for an objective measurement, and showcased a practical use of classical patient reported symptoms, regular arm circumference measurements to guide independent clinician assessment and grading per ISL staging. Patient education largely focused on typical signs and symptoms, risk factors that were supported by the latest evidence and avoided unnecessary precautionary advice.31,32,39 Specialised lymphedema therapy may also be a scarce resource and we defined specific referral criteria for right-siting patients to avoid taking up unnecessary resources. This improved the sustainability of the lymphedema surveillance strategy and allowed wider implementation.

A limitation of the study was the nature of the convenience sampling method and the relatively low frequency of moderate-to-severe BCRL observed. These could be due to sampling bias and retrospective nature of the study. To address this issue, the study used the cumulative prevalence diagnosed by either of the 3 assessment tools to include a larger sample of patients with possible BCRL. We accounted for the overestimation of BCRL by patient-reported symptoms and arm measurements compared to clinical BCRL that was likely due to the presence of other distracting conditions that warranted different management. This study did not claim to have a diagnostic gold standard for BCRL but highlighted the important aids to make an accurate clinical diagnosis.3 Although arm circumference measurement was relatively inexpensive, it required rigorous training of our staff to standardise the method of recording to improve accuracy and reduce inter-assessor variability. Educating on BCRL, addressing its risk factors, implementing regular surveillance, and timely referral for appropriate management remain cornerstone to any comprehensive lymphedema service.30 Based on our results, we could still generate important hypothesis on the risk factors relevant to our population, better understand the limitations of the current diagnostic process and plan for future research based on this set of standardised outcome assessment.

Future implications

We aim to safely reduce the morbidity of BCRL by providing the optimal breast cancer treatment necessary without compromising on oncological outcomes. This includes reviewing our patient selection criteria for various axilla therapies including axillary lymph node dissection or radiotherapy and to avoid practices deemed to be of low value.18

Fortunately, the observed severity of BCRL in our cohort was largely limited to subclinical and mild. These may be contributed by timely detection and referral for specialised therapy, although we would require a larger sample size and direct studies to confirm the effectiveness of our lymphedema surveillance strategy. Lastly, there is an emerging role for lymphatic preserving or restoring procedures that have shown promising results at reducing the severity of BCRL for those whose disease and treatment factors cannot be modified otherwise.40 However, it would require validation of other assessment tools to diagnose, assess the severity of lymphoedema, and progress following conservative or surgical treatment.39

CONCLUSION

In conclusion, our study showed that our rates of BRCL were comparable to international standards and highlighted similar patient profiles who were at risk of developing BCRL. Although the severity of BCRL were largely subclinical or mild, having a comprehensive lymphedema surveillance strategy is paramount to address and further reduce the impact of this debilitating condition.

Conflict of interest
None to declare.

Acknowledgement
The authors acknowledge and thank the rest of the breast care nurses and team in the Changi General Hospital Breast Centre.

Correspondence
Dr Jeffrey Jun Xian Hing, Breast Surgery, Changi General Hospital, Changi General Hospital, 2 Simei Street 3, Singapore 529889. E-mail: [email protected]

References

  1. Warren AG, Brorson H, Borud LJ, et al. Lymphedema: a comprehensive review. Ann Plast Surg 2007;59:464-72.
  2. Dayes IS, Whelan TJ, Julian JA, et al. Randomized trial of decongestive lymphatic therapy for the treatment of lymphedema in women with breast cancer. J Clin Oncol 2013;31:3758-63.
  3. DiSipio T, Rye S, Newman B, et al. Incidence of unilateral arm lymphoedema after breast cancer: a systematic review and meta-analysis. Lancet Oncol 2013;14:500-15.
  4. Shah C, Arthur DW, Wazer D, et al. The impact of early detection and intervention of breast cancer-related lymphedema: a systematic review. Cancer Med 2016;5:1154-62.
  5. Koelmeyer LA, Borotkanics RJ, Alcorso J, et al. Early surveillance is associated with less incidence and severity of breast cancer-related lymphedema compared with a traditional referral model of care. Cancer 2019;125:854-62.
  6. Kilgore LJ, Korentager SS, Hangge AN, et al. Reducing Breast Cancer-Related Lymphedema (BCRL) Through Prospective Surveillance Monitoring Using Bioimpedance Spectroscopy (BIS) and Patient Directed Self-Interventions. Ann Surg Oncol 2018;25:2948-52.
  7. Sekyere MO. Incidence and risk factors of arm lymphedema following breast cancer treatment. Journal of Global Oncology 2018;4:213s-213s.
  8. Cooper G, Bagnall A. Prevalence of lymphoedema in the UK: focus on the southwest and west midlands. Br J Community Nurs 2016;21:S6–S14.
  9. Torgbenu E, Luckett T, Buhagiar MA, et al. Prevalence and incidence of cancer related lymphedema in low and middle-income countries: a systematic review and meta-analysis. BMC Cancer 2020;20:604.
  10. Hara Y, Otsubo R, Shinohara S, et al. Lymphedema After Axillary Lymph Node Dissection in Breast Cancer: Prevalence and Risk Factors-A Single-Center Retrospective Study. Lymphat Res Biol 2022;20:600-6.
  11. McLaughlin SA, Wright MJ, Morris KT, et al. Prevalence of lymphedema in women with breast cancer 5 years after sentinel lymph node biopsy or axillary dissection: patient perceptions and precautionary behaviors. J Clin Oncol2008;26:5220-6.
  12. Armer J, Fu MR, Wainstock JM, et al. Lymphedema following breast cancer treatment, including sentinel lymph node biopsy. Lymphology2004;37:73-91.
  13. Lee WQ, Tan VKM, Choo HMC, et al. Factors influencing patient decision-making between simple mastectomy and surgical alternatives. BJS Open 2018;3:31-7.
  14. Sinnadurai S, Kwong A, Hartman M, et al. Breast-conserving surgery versusmastectomy in young women with breast cancer in Asian settings. BJS Open 2018;3:48-55.
  15. Tay MRJ, Wong CJ, Aw HZ. Prevalence and associations of axillary web syndrome in Asian women after breast cancer surgery undergoing a community-based cancer rehabilitation program. BMC Cancer 2021;21:1019.
  16. Kim YJ, Kim HJ, Chung SY, et al. Trends of axillary surgery in breast cancer patients with axillary lymph node metastasis: a comprehensive single-center retrospective study. Ann Surg Treat Res 2023;105:10-19.
  17. Cha C, Kim EY, Kim SY, et al. Impact of the ACOSOG Z0011 trial on surgical practice in Asian patients: trends in axillary surgery for breast cancer from a Korean Breast Cancer Registry analysis. World J Surg Onc 2022;20:198.
  18. Shubeck SP, Morrow M, Dossett LA. De-escalation in breast cancer surgery. NPJ Breast Cancer 2022;8:25.
  19. Giuliano AE, Ballman KV, McCall L, et al. Effect of Axillary Dissection vs No Axillary Dissection on 10-Year Overall Survival Among Women With Invasive Breast Cancer and Sentinel Node Metastasis: The ACOSOG Z0011 (Alliance) Randomized Clinical Trial. JAMA 2017;318:918-26.
  20. Mansel RE, Fallowfield L, Kissin M, et al. Randomized Multicenter Trial of Sentinel Node Biopsy Versus Standard Axillary Treatment in Operable Breast Cancer: The ALMANAC Trial. J Natl Cancer Inst 2006;98:599-609.
  21. Donker M, van Tienhoven G, Straver ME, et al. Radiotherapy or surgery of the axilla after a positive sentinel node in breast cancer (EORTC 10981-22023 AMAROS): a randomised, multicentre, open-label, phase 3 non-inferiority trial. Lancet Oncol 2014;15:1303-10.
  22. Lee J, Jung JH, Kim WW, et al. Ten-Year Oncologic Outcomes in T1-3N1 Breast Cancer After Targeted Axillary Sampling: A Retrospective Study. Ann Surg Oncol 2023;30:4669-77.
  23. Wong CJ, Tay MRJ, Aw HZ. Prevalence and Risk Factors of Adhesive Capsulitis in Asian Breast Cancer Patients Undergoing an Outpatient Community Cancer Rehabilitation Program. Arch Phys Med Rehabil 2021;102:843-8.
  24. Shin DJ, Nam KE, Song DH, et al. Carpal tunnel syndrome and tenosynovitis in women with breast cancer associated with hormone therapy: A multi-institutional analysis using a clinical data warehouse. Medicine (Baltimore) 2022;101:e28786.
  25. Zhi WI, Chen P, Kwon A, et al. Chemotherapy-induced peripheral neuropathy (CIPN) in breast cancer survivors: a comparison of patient-reported outcomes and quantitative sensory testing. Breast Cancer Res Treat 2019;178:587-95.
  26. Hyder T, Marino CC, Ahmad S, et al. Aromatase Inhibitor-Associated Musculoskeletal Syndrome: Understanding Mechanisms and Management. Front Endocrinol (Lausanne). 2021;12:713700.
  27. Strnad V, Hildebrandt G, Pötter R, et al. Accelerated partial breast irradiation: 5-year results of the German-Austrian multicenter phase II trial using interstitial multicatheter brachytherapy alone after breast-conserving surgery. Int J Radiat Oncol Biol Phys 2011;80:17.
  28. Beckwee D, Leysen L, Meuwis K, et al. Prevalence of aromatase inhibitor‐induced arthralgia in breast cancer: a systematic review and meta‐analysis. Supportive Care in Cancer 2017;25:1673‐86.
  29. Koehler LA, Haddad TC, Hunter DW, et al. Axillary web syndrome following breast cancer surgery: symptoms, complications, and management strategies. Breast Cancer (Dove Med Press) 2018;11:13-9.
  30. Fu MR. Breast cancer-related lymphedema: Symptoms, diagnosis, risk reduction, and management. World J Clin Oncol 2014;5:241-7.
  31. Armer JM, Hulett JM, Bernas M, et al. Best Practice Guidelines in Assessment, Risk Reduction, Management, and Surveillance for Post-Breast Cancer Lymphedema. Curr Breast Cancer Rep 2013;5:134-4.
  32. McLaughlin SA, DeSnyder SM, Klimberg S, et al. Considerations for Clinicians in the Diagnosis, Prevention, and Treatment of Breast Cancer-Related Lymphedema, Recommendations from an Expert Panel: Part 2: Preventive and Therapeutic Options. Ann Surg Oncol 2017;24:2827.
  33. Cemal Y, Pusic A, Mehrara BJ. Preventative measures for lymphedema: separating fact from fiction. J Am Coll Surg 2011;213:543-51.
  34. Asdourian MS, Skolny MN, Brunelle C, et al. Precautions for breast cancer-related lymphoedema: risk from air travel, ipsilateral arm blood pressure measurements, skin puncture, extreme temperatures, and cellulitis. Lancet Oncol 2016;17:e392-e405.
  35. Society for Ambulatory Anesthesia (SAMBA). Statement on Intravenous Catheter Placement, Venipuncture and Blood Pressure Measurements in the Ipsilateral Upper Extremity after Breast Cancer Surgery with and without Axillary Lymph Node Dissection. 21 September 2021. https://samba.memberclicks.net/assets/docs/SAMBA_Statements/SAMBA_Statement_IV-Breast-Surg.pdf. Accessed 19 October 2021.
  36. Ferguson CM, Swaroop MN, Horick N, et al. Impact of ipsilateral blood draws, injections, blood pressure measurements, and air travel on the risk of lymphedema for patients treated for breast cancer.J Clin Oncol 2016;34:691-8.
  37. Asdourian MS, Swaroop MN, Sayegh HE, et al. Association between precautionary behaviors and breast cancer-related lymphedema in patients undergoing bilateral surgery.J Clin Oncol 2017;35:3934-41.
  38. Kilbreath SL, Refshauge KM, Beith JM, et al. Risk factors for lymphoedema in women with breast cancer: A large prospective cohort.Breast 2016;28:29-36.
  39. International Society of Lymphology. The diagnosis and treatment of peripheral lymphedema: 2013 consensus document of the International Society of Lymphology.Lymphology 2013;46:1-11.
  40. Beederman M, Garza RM, Agarwal S, et al. Outcomes for Physiologic Microsurgical Treatment of Secondary Lymphedema Involving the Extremity. Ann Surg. 2022;276:e255-e263.