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Consequently, protein-rich fluid accumulates in the interstitial space, leading to abnormal swelling
[1,2]
and volume increase of the arm . In more advanced stages, lymphedema is characterized by adipose
[3]
deposition and irreversible fibrosis, together with residual lymphatic vessel disruption . Despite reported
[4]
incidence of BCRL being variable, DiSipio et al. referred the overall estimated incidence of upper limb
lymhedema after breast cancer to be 21.4%.

Symptoms of BCRL include arm heaviness, pain, impaired mobility, and recurrent skin and subcutaneous
tissue infections. BCRL also affects the patient’s body image with consequent psychological impairment [1,2,5] .
For this reason, it is one of the most disabling sequelae of breast cancer treatment.

Risk factors for BCRL can be non-treatment or treatment related. Non-treatment related risk factors
[8]
include BMI > 30 kg/m 2[6,7] , cellulitis and genetic predisposition [9,10] . In fact, several studies have suggested
that an underlying anomaly and/or dysregulation of the lymphatic system can lead to subclinical lymphatic
dysfunction. In turn, this would increase the risk of developing lymphedema after disruption of the
lymphatic network from surgery and/or radiation treatment. Treatment-related risk factors include axillary
[1]
surgery, mastectomy and lack of breast reconstruction, regional lymph node radiation, and chemotherapy .
[1]
One of the main treatment-related risk factors for BCRL is axillary lymph node dissection (ALND) as
[4]
it involves axillary clearance and thus, iatrogenic lymphatic damage. In a meta-analysis, DiSipio et al.
reported the incidence of BCRL in patients with unilateral breast cancer at 19.9% after ALND. On the
contrary, sentinel lymph node biopsy, an alternative procedure to ALND in clinically node negative breast
cancer patients, is reported to be associated with a four times lower incidence of BCRL compared to
ALND [4,11] . This is likely because sentinel lymph node biopsy is less invasive. On the other hand, several
studies have shown an increasing incidence of BCRL with the number of axillary nodes removed [12,13] .

Interestingly, mastectomy itself has been reported to be a risk factor for BCRL [1,4,12] . Regarding breast
reconstruction, some studies suggest that delayed autologous breast reconstruction can improve existing
[14]
[11]
lymphedema . Card et al. concluded in a 6-year study that patients undergoing breast reconstruction
after mastectomy had a lower risk of, and later onset of BCRL compared to patients who had undergone
[11]
mastectomy alone. Card et al. also found no difference in the risk of BCRL between the different types
of breast reconstruction (tissue expander/implant, latissimus dorsi and implant, free autologous abdominal
tissue only). The authors thus hypothesized that the transfer of vascularized tissue onto the chest reduces
scarring, bridges damaged lymphatic vessels and promotes angiogenesis [11,14] . With regard to expander/
implant based breast reconstruction, tissue expansion and capsule formation seem to increase the
expression of vascular endothelial growth factor (VEGF), which has an important role in angiogenesis and
[15]
[10]
lymphangiogenesis , via chronic ischemia .
Regional lymph node radiation (supraclavicular, with or without posterior axillary boost) is an independent
risk factor for BCRL. It also conveys an increased risk of developing BCRL compared to breast/chest
[16]
radiotherapy alone .
In terms of the role of adjuvant and neoadjuvant chemotherapy in increasing BCRL risk, a literature review
[1]
by Gillespie et al. [Figure 1] suggested that the current evidence was not conclusive because several
studies have chemotherapy as a potential risk factor for BCRL but data from others were non-confirmatory.

Several staging systems have been proposed for lymphedema. One of the most widely used is that
[17]
of the International Society of Lymphology (ISL), as shown in Table 1 . Early or mild stages can be
characterized by a positive “pitting” test, when pressure exerted to an edematous limb by the thumb for at
least 60 seconds induces a depression or indentation on the skin. Such indentation is attributable to the
displacement of interstitial fluid. In more advanced stages, when adipose hypertrophy is dominant in the
[18]
affected limb, edema is typically “non-pitting” .