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Page 2 of 9 Minasian et al. Plast Aesthet Res 2022;9:18 https://dx.doi.org/10.20517/2347-9264.2021.128

underdiagnosed disease.

Lymphedema results from a malformation, insult, injury, or obstruction of the lymphatic system and can be
classified as primary or secondary. The most common cause of secondary lymphedema in developed
[1,2]
countries is lymphadenectomy and radiation for cancer treatment, at approximately 1 in 1000 . Primary
lymphedema caused by a malformation or repair defect of the lymphatic system is rare, with an estimated
[3]
prevalence of 1 in 100,000 . The population frequency of PTL has not been studied but uses persistent limb
swelling after trauma as a proxy, and the incidence may be as high as 20% .
[4,5]

While iatrogenic lymphedema has been well-characterized and studied, the available descriptions of PTL
consist mainly of case reports and case series, as well as more recent articles discussing specific approaches
to diagnosing and treating PTL with a focus on restoration of lymphatic function. This review synthesizes
the available data in an attempt to help further advance the understanding and management of patients with
PTL, and ultimately improve their quality of life and outcomes.

LYMPHATIC RESPONSE TO TRAUMATIC INJURY
Injuries to bone and soft tissues are usually followed by edema, which develops immediately after soft tissue
injury or fracture . Unlike edema from chronic venous obstruction, post-traumatic edema presents with
[6]
pain at the site of injury, erythema, and increased skin temperature. These clinical findings are indicative of
a protracted inflammatory reaction characterized by immune cell infiltration and activation of an
inflammatory cascade .
[6,7]
A prospective study of 21 patients with post-traumatic lower extremity edema demonstrated dilated
lymphatics with the decreased lymphatic flow on lymphoscintigraphy . Minor trauma, however, seldom
[6]
leads to chronic lymphedema. Post-traumatic edema and acute PTL are part of the normal physiologic
wound healing process, occurring up to three months following trauma and is a consequence of the
[8]
inflammatory response . The lymphatic system undergoes repair during this period through
lymphangiogenesis. Transient direct pressure on initial and terminal lymphatics in an experimental setting
temporarily damages lymphatics, but lymphatic function is eventually restored . Occasionally, as wound
[9]
healing progresses, scar tissue may develop and restrict the continuous flow of the lymphatic vessels, leading
to lymphatic dysfunction . In these instances, lymphedema can persist past the physiologic three months
[10]
and become pathologic.

In chronic cases, upstream lymphatics begin progressing through three histopathological stages as a
consequence of the downstream injury . In stage 1, lymphatic channels dilate and interstitial protein
[11]
deposition incites inflammation. In stage 2, inflammation stimulates contraction and luminal narrowing
due to smooth muscle cell and collagen deposition. Stage 3 is marked by sclerosis and vessel obliteration.

The clinical progression of lymphedema is described by the International Society of Lymphology staging
system . In stage 0, despite a normal clinical exam, there is asymptomatic lymphatic damage which can be
[12]
detected on lymphoscintigraphy or impedance spectroscopy. Stage 1 is clinically visible, but reversible since
excess volume comprises lymphatic fluid accumulation secondary to downstream obstruction. This
manifests as pitting edema responsive to elevation and compression. In stage II, irreversible changes are
noted as interstitial protein deposition, and a macrophage-induced inflammatory state causes tissue fibrosis
and fat deposition. Clinically, swelling is not fully reversible and becomes non-pitting. Patients can
experience limb heaviness and discomfort. Stage III denotes a markedly enlarged limb with hardened,
fibrotic tissue, which can become unusually tender to touch. Patients with persistent PTL in particular often