Lymphedema

When lymphatic impairment becomes so great that the collected lymph fluid exceeds the lymphatic system's ability to transport it, an abnormal amount of protein-rich fluid collects in the tissues. Left untreated, this stagnant, protein-rich fluid causes tissue channels to increase in size and number, reducing oxygen availability. This interferes with wound healing and provides a rich medium for bacterial growth which can result in skin infections, lymphangitis, lymphadenitis, and, in severe cases, skin ulcers.[4] It is vital for lymphedema patients to be aware of the symptoms of infection and to seek immediate treatment, since recurrent infections or cellulitis, in addition to their inherent danger, further damage the lymphatic system and set up a vicious circle.

In rare cases, lymphedema may lead to a form of cancer called lymphangiosarcoma, although the mechanism of carcinogenesis is not understood. Lymphedema-associated lymphangiosarcoma is called Stewart–Treves syndrome.[4] Lymphangiosarcoma most frequently occurs in cases of long-standing lymphedema. The incidence of angiosarcoma five years after radical mastectomy is estimated to be 0.45% in surviving patients.[5][6] Lymphedema is also associated with a low grade form of cancer called retiform hemangioendothelioma (a low grade angiosarcoma).[7]

Lymphedema can be disfiguring, and may result in a poor body image and psychological distress.[8] Complications of lymphedema can cause difficulties in activities of daily living.[9]

Lymphedema is most commonly seen after lymph node dissection, surgery or radiation therapy for the treatment of cancer, most notably breast cancer. In many patients the condition does not develop until months or even years after therapy has concluded. Lymphedema may also be associated with accidents or certain diseases or conditions that may inhibit the lymphatic system from functioning properly.[4] It can also be caused by damage to the lymphatic system from infections such as cellulitis.[12] In tropical areas of the world where parasitic filarial worms are endemic, a common cause of secondary lymphedema is filariasis.[13]

Primary lymphedema may be congenital or may arise sporadically. Multiple syndromes are associated with primary lymphedema, including Turner syndrome, Milroy's disease, and Klippel–Trénaunay syndrome. In these syndromes it may occur as a result of absent or malformed lymph nodes and/or lymphatic channels. Lymphedema can be present at birth, develop at the onset of puberty (praecox), or not become apparent for many years into adulthood (tarda). In men, lower-limb primary lymphedema is most common, occurring in one or both legs. Some cases of lymphedema may be associated with other vascular abnormalities.[4]

Secondary lymphedema affects both men and women, and, in Western countries, is most commonly due to cancer treatment.[14] In women, it is most prevalent in an upper limb after breast cancer surgery, especially axillary lymph node dissection,[15] and occurs on the same side of the body as the surgery. Breast and trunk lymphedema can also occur but go unrecognised as there is swelling in the area after surgery, and its symptoms (peau d'orange and an inverted nipple) can be confused with post surgery fat necrosis.[16] Between 38 and 89% of breast cancer patients have lymphedema due to axillary lymph node dissection or radiation.[14][17][18] Unilateral lymphedema of a lower limb occurs in up to 41% of patients after gynecologic cancer.[14][19] For men treated for prostate cancer, a 5-66% incidence has been reported, with the incidence rate depending on whether staging or radical removal of lymph glands was done in addition to radiotherapy.[14][20][21]

Head and neck lymphedema can be caused by surgery or radiation therapy for tongue or throat cancer. It may also occur in the lower limbs or groin after surgery for colon, ovarian or uterine cancer, if removal of lymph nodes or radiation therapy is required. Surgery or treatment for prostate, colon and testicular cancers may result in secondary lymphedema, particularly when lymph nodes have been removed or damaged.

The onset of secondary lymphedema in patients who have had cancer surgery has also been linked to aircraft flight (likely due to decreased cabin pressure or relative immobility). For cancer survivors wearing a prescribed and properly fitted compression garment may help decrease swelling during air travel.[22]

Some cases of lower-limb lymphedema have been associated with the use of tamoxifen, due to blood clots and deep vein thrombosis (DVT) associated with this medication. Resolution of the blood clots or DVT is needed before lymphedema treatment can be initiated.

Hereditary lymphedema is a primary lymphedema – swelling that results from abnormalities in the lymphatic system that are present from birth. Swelling may be present in a single limb, several limbs, genitalia, or the face. It is sometimes diagnosed prenatally by a nuchal scan or postnatally by lymphoscintigraphy.

The most common cause is Meige disease which usually presents at puberty. Another form of hereditary lymphedema is Milroy's disease, caused by mutations in the VEGFR3 gene.[4][23] Hereditary lymphedema is frequently syndromic and is associated with Turner syndrome, lymphedema–distichiasis syndrome, yellow nail syndrome, and Klippel–Trénaunay syndrome.[24]

One defined genetic cause for hereditary lymphedema is GATA2 deficiency. This deficiency is a grouping of several disorders caused by a single defect: familial or sporadic inactivating mutations in one of the two parental GATA2 genes. These autosomal dominant mutations cause a reduction, i.e. a haploinsufficiency, in the cellular levels of the gene's product, GATA2. The GATA2 protein is a transcription factor critical for the development, maintenance, and functionality of blood-forming, lympathic-forming, and other tissue-forming stem cells. Due to these mutations cellular levels of GATA2 are deficient and over time individuals develop hematological, immunological, lymphatic, and other disorders. GATA2 deficiency-induced defects in the lymphatic vessels and valves underlies the development of lymphedema, primarily in the lower extremities but may also occur in places such as the face or testes. This form of the deficiency, when coupled with sensorineural hearing loss, which may also be due to faulty development of the lymphatic system, is sometimes termed Emberger syndrome.[25][26]

Primary lymphedema occurs in approximately 1-3 births out of every 10,000 births, with a female to male ratio of 3.5:1. In North America, the incidence of primary lymphedema is approximately 1.15 births out of every 100,000 births. Compared to secondary lymphedema, primary lymphedema is relatively rare.[27]

Bilateral lower extremity inflammatory lymphedema (BLEIL) is a distinct type of lymphedema occurring in a setting of acute and prolonged standing, such as in new recruits during basic training.[28] Possible underlying mechanisms may include venous congestion and inflammatory vasculitis.[29]

Cheng's Lymphedema Grading

The International Society of Lymphology (ISL) Staging System is based solely on subjective symptoms, making it prone to substantial observer bias. Imaging modalities have been suggested as useful adjuncts to the ISL staging to clarify the diagnosis, such as Cheng's Lymphedema Grading tool, which assesses the severity of extremity lymphedema based on objective limb measurements and provides appropriate options for management.[34][35][36]

Severity of upper extremity lymphedema in different stages[37]

Severity of lower extremity lymphedema in different stages[37]

• Grade 1: Spontaneously reversible on elevation. Mostly pitting edema.
• Grade 2: Non-spontaneously reversible on elevation. Mostly non-pitting edema.
• Grade 3: Gross increase in volume and circumference of Grade 2 lymphedema, with eight stages of severity given below based on clinical assessments.

As described by the Fifth WHO Expert Committee on Filariasis,[38][39] and endorsed by the American Society of Lymphology,[40] the staging system helps to identify the severity of lymphedema. With the assistance of medical imaging, such as MRI or CT, staging can be established by the physician, and therapeutic or medical interventions may be applied:

• Stage 0: The lymphatic vessels have sustained some damage that is not yet apparent. Transport capacity is sufficient for the amount of lymph being removed. Lymphedema is not present.
• Stage 1 : Swelling increases during the day and disappears overnight as the patient lies flat in bed. Tissue is still at the pitting stage: when pressed by the fingertips, the affected area indents and reverses with elevation. Usually, upon waking in the morning, the limb or affected area is normal or almost normal in size. Treatment is not necessarily required at this point.
• Stage 2: Swelling is not reversible overnight, and does not disappear without proper management. The tissue now has a spongy consistency and is considered non-pitting: when pressed by the fingertips, the affected area bounces back without indentation. Fibrosis found in Stage 2 lymphedema marks the beginning of the hardening of the limbs and increasing size.
• Stage 3: Swelling is irreversible and usually the limb(s) or affected area becomes increasingly large. The tissue is hard (fibrotic) and unresponsive; some patients consider undergoing reconstructive surgery, called "debulking". This remains controversial, however, since the risks may outweigh the benefits and further damage done to the lymphatic system may make the lymphedema worse.
• Stage 4: The size and circumference of the affected limb(s) become noticeably larger. Bumps, lumps, or protrusions (also called knobs) on the skin begin to appear.
• Stage 5: The affected limb(s) become grossly large; one or more deep skin folds is present.
• Stage 6: Knobs of small elongated or rounded sizes cluster together, giving mossy-like shapes on the limb. Mobility of the patient becomes increasingly impaired.
• Stage 7: The person becomes "handicapped", and is unable to independently perform daily routine activities such as walking, bathing and cooking. Assistance from the family and health care system is needed.

Lymphedema can also be categorized by its severity (usually compared to a healthy extremity):[41]

• Grade 1 (mild edema): Involves the distal parts such as a forearm and hand or a lower leg and foot. The difference in circumference is less than 4 cm (1.6 in) and no other tissue changes are present.
• Grade 2 (moderate edema): Involves an entire limb or corresponding quadrant of the trunk. Difference in circumference is 4–6 cm (1.6–2.4 in). Tissue changes, such as pitting, are apparent. The patient may experience erysipelas.
• Grade 3a (severe edema): Lymphedema is present in one limb and its associated trunk quadrant. Circumferential difference is greater than 6 cm (2.4 in). Significant skin alterations, such as cornification, keratosis, cysts or fistulae, are present. Additionally, the patient may experience repeated attacks of erysipelas.
• Grade 3b (massive edema): The same symptoms as grade 3a, except that two or more extremities are affected.
• Grade 4 (gigantic edema): In this stage of lymphedema, the affected extremities are huge, due to almost complete blockage of the lymph channels.

Lymphedema should not be confused with edema arising from chronic venous insufficiency, which is caused by compromise of venous drainage rather than lymphatic drainage. However, untreated venous insufficiency can progress into a combined venous/lymphatic disorder known as phlebetic lymphedema (or phlebolymphedema).[42][43][44]

Lymphedema compression sleeve on a mannequin

Once a person is diagnosed with lymphedema, compression becomes imperative in the management of the condition. Garments are often intended to be worn all day but may be taken off for sleep, unless otherwise prescribed. Elastic compression garments are worn on the affected limb following complete de-congestive therapy to maintain edema reduction. Inelastic garments provide containment and reduction.[2] Available styles, options, and prices vary widely. A professional garment fitter or certified lymphedema therapist can help determine the best option for the patient.

Compression bandaging, also called wrapping, is the application of layers of padding and short-stretch bandages to the involved areas. Short-stretch bandages are preferred over long-stretch bandages (such as those normally used to treat sprains), as the long-stretch bandages cannot produce the proper therapeutic tension necessary to safely reduce lymphedema and may produce a tourniquet effect. Compression bandages provide resistance that assists in pumping fluid out of the affected area during exercise. This counter-force results in increased lymphatic drainage and therefore a decrease in size of the swollen area.[47]

Intermittent pneumatic compression therapy (IPC) utilizes a multi-chambered pneumatic sleeve with overlapping cells to promote movement of lymph fluid.[2] Pump therapy should only be used in addition to other treatments such as compression bandaging and manual lymph drainage. Pump therapy has been used in the past to help with controlling lymphedema. In some cases, pump therapy helps soften fibrotic tissue and therefore potentially enable more efficient lymphatic drainage.[48] However, reports link pump therapy to increased incidence of edema proximal to the affected limb, such as genital edema arising after pump therapy in the lower limb.[49] Current literature has suggested the use of IPC treatment in conjunction with an elastic therapeutic tape is more effective in the overall reduction of lymphedema as well as increasing shoulder range of motion than the traditional treatment of IPC paired with complete decongestive therapy. The tape is an elastic cotton strip with an acrylic adhesive that is used commonly used to relieve the discomfort and disability associated with sports injuries, but in the context of lymphedema, this increases the space between the dermis and the muscle which increases the opportunity for lymphatic fluid to flow out naturally.[50] The use of IPC treatments with tape, as well as subsequent lymphatic drainage, has proven to significantly reduce the circumference of lymphatic limbs in patients experiencing lymphedema secondary to breast cancer post-mastectomy.[50]

In those with lymphedema or at risk of developing lymphedema, such as following breast cancer treatment, resistance training did not increase swelling and led to decreases in some, in addition to other potential beneficial effects on cardiovascular health.[51][52] Moreover, resistance training and other forms of exercise were not associated with an increased risk of developing lymphedema in people who previously received breast cancer-related treatment. Compression garments should be worn during exercise.[53]

Physical therapy for patients with lymphedema may include trigger point release, soft tissue massage, postural improvement, patient education on condition management, strengthening, and stretching exercises. Exercises may increase in intensity and difficulty over time, beginning with passive movements to increase range of motion and progressing towards using external weights and resistance in various postures.[47]

The treatment of lymphedema is usually conservative, however the use of surgery is proposed for some cases.[54]

Suction assisted lipectomy (SAL), also known as liposuction for lymphedema, may help improve chronic non pitting edema.[55] The procedure removes fat and protein and is done alongside continued compression therapy.[55]

Vascularized lymph node transfers (VLNT) and lymphovenous bypass are supported by tentative evidence as of 2017 but are associated with a number of complications.[2]

Low-level laser therapy (LLLT) was cleared by the US Food and Drug Administration (FDA) for the treatment of lymphedema in November 2006.[56] According to the US National Cancer Institute, LLLT may be effective in reducing lymphedema in some women. Two cycles of laser treatment were found to reduce the volume of the affected arm in approximately one-third of people with post-mastectomy lymphedema at three months post-treatment.[57][58]