Lymphedema is the pathologic accumulation of fluid in the soft tissues due to impaired lymphatic drainage, with resultant inflammation, adipose tissue hypertrophy, and fibrosis. It can be either primary or secondary, caused by surgery or disease processes. Regional swelling and induration can cause disfigurement. Treatment can prove difficult in many instances.

Epidemiology

Most cases of primary lymphedema are sporadic; the rest are hereditary or associated with other congenital conditions (see below).

There has been a growing prevalence of secondary lymphedema due to the large number of patients undergoing breast and pelvic surgery and/or receiving radiation therapy, so much so that in the developed world, secondary lymphedema due to iatrogenic causes constitute the majority of cases.

Pathology

Lymphedema occurs from interstitial and lymphatic fluid accumulation within the skin and subcutaneous tissue. This stimulates fibroblasts, keratinocytes, and adipocytes, which in turn result in the deposition of collagen and glycosaminoglycans within the skin and subcutaneous tissue. This could then lead to skin hypertrophy and the destruction of elastic fibers.

It has traditionally been defined as interstitial edema and protein accumulation due to a defect in lymphatic drainage. However, recent findings suggest that the interstitial protein concentration may be low in some types of lymphedema.

Etiology

Lymphedema is broadly classified into primary and secondary forms.

Primary lymphedema

Due to an inherent defect in the lymphatic vessels or lymph nodes.

• hereditary lymphedema and hereditary associated conditions ⁶

  • chromosomal aneuploidy

    • Klinefelter syndrome: most commonly

    • Turner syndrome

    • trisomy 21 (Down syndrome)

    • trisomy 13 (Patau syndrome)

    • trisomy 18 (Edwards syndrome)

  • dysmorphogenic disturbances

    • Milroy disease

    • Klippel-Trénaunay syndrome

    • Noonan syndrome

    • neurofibromatosis type 1

    • lymphedema-hypothyroidism syndrome

    • Meige disease

    • distichiasis lymphedema

• sporadic: overall, more common than hereditary lymphedema

Primary lymphedema can be further classified clinically and lymphangiographically (for the latter, see 'Radiographic features' below).

Clinical classification is based on the age of onset:

• congenital lymphedema: onset within 2 years of birth (comprises ~10% of all primary forms) ^7,8

  • autosomal dominant: Milroy disease

  • familial, non-dominant

  • sporadic: most common

• lymphedema praecox: manifests between ages 2-35 (~85%), much more common in females (female to male ratio of 10:1) ^ref

  • autosomal recessive: Meige disease

  • sporadic: much more common

• lymphedema tarda: manifests after age 35 (~10%) ^ref

Secondary lymphedema

Arises from obstruction or disruption of the lymphatic system, either to the lymph nodes or to the lymphatic channels

• lymph node level

  • iatrogenic: lymphatic pathway fibrosis due to surgery or radiation therapy

    • arm lymphedema: after axillary lymph node dissection (ALND) at mastectomy

    • pelvic lymphedema: after pelvic lymph node dissection (PLND) at surgery (e.g. for urinary bladder carcinoma)

    • neck lymphedema

  • neoplasia

    • breast cancer

    • cervical cancer

    • Hodgkin lymphoma

    • melanoma

    • prostate cancer

    • metastatic disease

• lymphatic channels

  • surgical, e.g. iliofemoral bypass surgery

  • injury

  • radiation-induced fibrosis

  • neoplastic infiltration

  • rheumatoid arthritis

  • filariasis

  • elephantiasis nostras verrucosa

  • recurrent infection, e.g. cellulitis, lymphangitis, trichophytosis ⁹

Radiographic features

Diagnosis is usually a straightforward clinical one in advanced chronic disease, though imaging is used for confirming the diagnosis, for surgical planning, and intraoperatively. In early or intermittent disease, on the other hand, diagnosis can prove difficult.

Nuclear medicine

Lymphoscintigraphy is commonly used for confirming the diagnosis of lymphedema and is a reliable method for functional assessment of the lymphatic system. It affords visualization of the major lymphatic trunks and lymph nodes as well as evaluation of lymphatic function. ^99mTc-sulfur colloid radiotracer is injected into the interdigital web space of the afflicted limb, either intradermally or subdermally. Using stress tests, it is possible to quantify the rate of tracer disappearance from the injection site and its accumulation within the lymph nodes. Typical abnormalities in lymphedema include ^10,11:

• dermal back-flow

• absent or delayed radiotracer transport

• crossover filling with retrograde back-flow

• absent or delayed lymph node visualization

MRI

Magnetic resonance lymphography (MRL) entails the acquisition of
high-resolution 3D datasets of the entire limb. It is especially useful for preoperative planning of lymphaticovenular anastomosis (LVA) supermicrosurgery, as it can demonstrate individual lymphatic channels and areas of dermal backflow ¹².

An MR lymphography exam comprises two sequences:

1. 3D heavily T2-weighted: shows severity and distribution of lymphedema

2. postcontrast high-resolution fat-suppressed 3D spoiled gradient echo (SPGR) after intracutaneous contrast injection: depiction of lymphatic channels

Finally, an MR venogram (also high-resolution 3D SPGR) may also be obtained after intravenous contrast injection to further facilitate the differentiation of superficial veins from lymphatic channels.

Indocyanine green lymphangiography

Indocyanine green (ICG) lymphangiography is an emerging technique. It rivals MR lymphography for its sensitivity and specificity in diagnosing lymphedema, and is better than traditional lymphoscintigraphy for it ^13,14.

CT

CT can be used to localize edema as subfascial or epifascial and depict the characteristic honeycomb pattern of subcutaneous edema and skin thickening. Its role in follow-up is diminishing, though, owing to its inherent ionizing radiation ^ref.