Lymphedema is the build-up of proteinaceous fluid within the interstitial compartment secondary to an imbalance of lymphatic fluid production and its clearance by the lymphatic transport system. Although estimates vary in the literature, lymphedema probably affects in excess of 200 million people worldwide. The most common cause by far is the parasite Wuchereria bancrofti, which is estimated to affect more than 90 million people worldwide. (Again, this varies in the literature, as it is difficult to accurately record incidence in many developing countries.) This parasitic disease, transmitted by mosquitoes, results in adult filarial worms physically blocking lymphatic channels. The World Health Organization (WHO) has implemented major programs to target the problem of filariasis.1 The lower limb is affected far more commonly than any other site. The ratio between lower to upper limb involvement is 9:1 across all causes. Lymphedema is not, however, limited to the limbs and genitalia, as it can occur in the head and neck region in patients treated for head and neck cancer.2 In the developed world, the most common cause of secondary lymphedema is malignancy.3 This occasionally occurs secondary to a primary tumor but is far more common after surgical excision or radiotherapy of tumor or lymph node basins. Between 25 and 50% of patients develop lymphedema of the ipsilateral upper limb after mastectomy. Lymph node dissection can lead to lymphedema in up to 70% of cases depending on anatomic site, while even sentinel lymph node biopsy is associated with rates of up to 10%.
2. Deng J, Ridner SH, Dietrich MS, et al. Prevalence of secondary lymphedema in patients with head and neck cancer. J Pain Symptom Manage 2012;43(2):244–252
3. Warren AG, Brorson H, Borud LJ, Slavin SA. Lymphedema: a comprehensive review. Ann Plast Surg 2007;59(4):464–472 PHYSIOLOGY OF THE LYMPHATIC SYSTEM 2. Which one of the following statements is correct regarding the lymphatic system? Although muscle itself does not have lymphatic channels, it serves an important role in lymphatic function by moving lymph from areas of low to high pressure. The propulsion of lymph relies on valves within the lymphatic system combined with both smooth muscle in the vessels themselves, and skeletal muscle externally compressing the vessels to propel fluid from the periphery to the trunk. Other modalities of propulsion are arterial and respiratory movements. The lymphatic system is derived embryologically from the venous system and serves to move fluid, proteins, and lipids from the interstitial space into the venous system (not away from it). The lymphatic system contains both deep and superficial components. Some channels such as those within the dermis contain valves. The superficial components drain into the deep components at three main sites: the cubital fossa, the inguinal fossa, and the popliteal fossa. The cisterna chyli is a sac at the level of L1–L2 that receives lymphatic drainage from the lower limbs and trunk. From the cisterna, lymph travels within the thoracic duct from T12 and drains into the confluence of the left internal jugular and left subclavian veins. Knowledge of this anatomy is clinically relevant when undertaking a neck dissection, as damage to the lymphatic system here can result in a chyle leak. The lymphangion is the functional unit of the lymphatic system but is noncontractile. While blood vessels have a defined basement membrane, lymphatics have several intercellular gaps that allow movement of fat and proteins into the lymphatics.1–3
4. Douglass J, Kelly-Hope L. Comparison of staging systems to assess lymphedema caused by cancer therapies, lymphatic filariasis, and podoconiosis. Lymphat Res Biol 2019;17(5): 550–556 Primary lymphedema most commonly affects the lower limbs and can be unilateral or bilateral. It is classified by age of onset as congenital (younger than 2 years), praecox (puberty), or tarda (35 years of age).1,2 Of these, lymphedema tarda is the rarest subtype (<10%) and lymphedema praecox is the most common, representing up to 80% of all primary lymphedema. Milroy’s disease refers to lymphedema congenita and affects females more commonly than males with a 2:1 ratio. It usually presents with bilateral lower limb lymphedema in children before their second birthday. The inheritance pattern for primary lymphedema varies depending on subtype and is most commonly autosomal dominant, but can be sporadic in Milroy’s disease. Wolfe and Kinmonth3 have classified primary lymphedema as anaplastic, hypoplastic, or hyperplastic based on the appearance during lymphangiography. Hypoplastic lymphedema is the most common subtype (67% of cases) and can be obstructive or nonobstructive.
The history suggests this patient has Meige’s syndrome, which is a type of primary lymphedema occurring in puberty that usually presents as new-onset unilateral lymphedema affecting the foot and calf. Associated inflammation is often present, and this can be complicated by cellulitis. Associated abnormalities include vertebral and cerebrovascular malformations, sensorineural (as opposed to conductive) hearing loss, and a double row of eyelashes (distichiasis). The latter can result from abnormal development of the meibomian glands. Meige’s disease is also known as familial lymphedema praecox and more typically affects females with a ratio of 4:1. It is the most common form of primary lymphedema representing 65–80% of cases.1–2
The term pseudosarcoma relates to a massive local edema in severely obese patients where there are folds of fat that compress the lymphatics and lead to a thickened epidermis with dermal fibrosis. The most common anatomic location is the medial thigh but this process can also occur in the abdomen in the presence of a large panniculus.1,2 Erysipelas refers to a streptococcal dermal infection that can be seen in patients with lymphedema. Infection of the lymphatics is often a problem in patients with lymphedema and is termed lymphangitis. This tends to start distally. Lymphangiosarcoma is a rare form of soft tissue cancer that can occur in patients with chronic lymphedema. Cellulitis is also a frequent complication in lymphedema patients and may be seen in association with lymphangitis. Infections are generally managed well with short courses of intravenous targeted antibiotics.1–3
patient? There are a range of signs that should be noted during examination of a patient with suspected lymphedema. The Stemmer sign is elicited by attempting to pinch skin over the dorsum of the second toe. This will not be possible in a patient with significant lymphedema. Other clinical findings are not specific to the lower limb and include doughy swelling, peau de orange skin changes, and circumferential limb measurements with a side-to-side difference greater than 2 cm. Assessing whether the edema is pitting or nonpitting is also important, as well as looking for evidence of active infection such as cellulitis or lymphangitis. The peau de orange sign is due to swelling within the dermis.1–3
Lymphoscintigraphy is currently considered to be the benchmark for diagnosing lymphedema, although other modalities can be very useful in some circumstances.1 For example, where deep venous thrombosis or chronic vascular disease is suspected, an ultrasound examination is useful. If malignancy is suspected, then CT or MRI may be helpful. Each of these modalities has a high sensitivity and specificity in confirming the diagnosis of lymphedema while facilitating tumor identification. An MRI is particularly good for providing detail of lymphatic architecture and preventing radiation exposure. Because of the success of these less-invasive imaging modalities, contrast lymphangiography is no longer commonly performed. Lymphoscintigraphy involves injection of nonionizing contrast agent (Tc 99M, Tc 99m-HAS, or Tc 99m dextran) into the interstitial space. It can help to assess the function of the lymphatic channels and drainage of lymph to nodal basins. The downside is that poor resolution prohibits anatomic evaluation and it is unable to quantify changes in the limb. Furthermore, it is generally not useful in planning lymphaticovenular anastomoses, and for this purpose, CT is better. Lastly, it requires injection which can be painful for patients.1–3
cancer? It is a myth that venipuncture should not be performed on the affected side after treatment of the axilla (particularly in breast cancer patients), because it will exacerbate lymphedema or result in infection. Green et al1 reviewed literature from 1966 to 2004 and found no evidence to support this common dictum. They stated that the main theoretical risk for patients with lymphedema having cannulation is the introduction of infection, leading to cellulitis and further lymphatic damage. They found no evidence that aseptic placement of a cannula or needle will regularly cause infection or that such an approach will worsen or exacerbate lymphedema. Injections are required for lymphoscintigraphy, lymphangiography, and liposuction, yet these are not regularly complicated by cellulitis or worsening of lymphedema. In the absence of robust evidence, the alternative limb should probably be used preferentially. However, the affected side can be considered for safe use in venipuncture when required. van der Veen et al2 attempted to identify risk factors for the development of lymphedema after breast surgery with axillary clearance. In a cohort of 245 women, they found that risk increased with body mass index (BMI) over 25, axillary radiotherapy, and pathologic lymph node status. In general, the greatest risk of developing lymphedema is after mastectomy but is still high after a lumpectomy or axillary node surgery. The rates of lymphedema following sentinel lymph node biopsy (SNLB) and axillary clearance differ significantly with rates after SNLB of up to 10% compared with rates of up to 65% after full axillary clearance. This does, however, make the point that patients must be aware of the risk of lymphedema with SNLB particularly as this is only a staging/ diagnostic procedure yet carries this risk. In contrast although the risk of lymphedema is far higher with formal lymph node dissection, this is a treatment procedure.
The description given is suspicious for development of a new malignancy and this is likely to be Stewart-Treves syndrome. This is a type of lymphangiosarcoma arising within chronic lymphedema, classically described after radical mastectomy. It is difficult to treat and has a very poor prognosis (life expectancy is less than 18 months after diagnosis). Wide local resection of the tumor is the preferred treatment modality.1 Erysipelas and lymphangitis both present with a red swollen limb and would not be expected to display the above features. Breast cancer more commonly would metastasize to the lungs, bone, or liver, although it may recur locally in the chest wall. The term pseudosarcoma refers to massive local edema in severely obese patients where folds of fat compress the lymphatics leading to edema, thickened epidermis, and dermal fibrosis. It most commonly occurs on the thighs.
Ivermectin is the drug of choice used for treatment of filariasis and is used in the World Health Organization (WHO) program.1 It is a broad-spectrum antiparasitic agent that may be combined with albendazole in the case of coendemicity with onchocerciasis (another parasitic disease transmitted by black flies that can lead to skin disease and blindness). The other treatment option is to use diethylcarbamazine citrate with albendazole. Suramin is another antiparasitic drug that was developed almost 100 years ago. It is used to treat trypanosomes (sleeping sickness). Mebendazole is a drug used to treat parasitic worm infections such as threadworms (Enterobius vermicularis), roundworm (ascariasis), or hook worm (Ancylostoma). Penicillin is a broad-spectrum antibiotic derived from penicillium molds, first discovered in 1928 and used for a variety of soft tissue, visceral, and bone infections. Erythromycin is another antibiotic with similar indications to penicillin but for individuals with a penicillin allergy.1,2
Complete decongestive therapy (CDT) can be very effective for managing lymphedema and reducing volume by 40–60% in patients with pitting edema. It is the benchmark first-line treatment for lymphedema as in this case and is administered by a certified lymphedema therapist. It combines an initial volume reduction phase of 3–8 weeks (involving manual drainage, exercise, skin care, elastic compression, and patient education delivered by therapist) with a maintenance phase of self-administered lymph drainage, exercise, skin care, and compression garments. A compression garment alone is far less effective than these combined measures. Circumferential liposuction can be extremely effective at reducing volume in lymphedema. It is best indicated where there is a volume excess largely due to fat hypertrophy and there is minimal pitting. The caveat of liposuction is that lifelong compression must be used to maintain the results. It would not be the first-line treatment, however, as CDT would be undertaken first.1-3 The Charles procedure is a procedure described by Charles in 1912. It involves radical, circumferential excision of skin and lymphedematous tissue above the deep fascial layer with immediate split-thickness skin grafting, much like the management of deep burn injury. This is clearly a very deforming undertaking and is not commonly used in clinical practice.4 The modified Charles procedure stages the reconstruction using split-thickness skin grafts with temporization of the wounds with negative pressure therapy. Skin grafts are then applied at 1 week.5
The Barcelona algorithm for the management of lymphedema aims to guide clinicians on decision-making for surgery in lymphedema (Fig. 69.1).1 As can be seen from the figure, clinical assessment and imaging must be performed first. The recommended imaging includes indocyanine green (ICG) lymphography, lymphoscintigraphy, and MRI lymphography. This should provide information on the nature of the cause. If there is a functional lymphatic system, then a decision needs to be made as to whether there is impairment of lymphatic flow through the axilla or not. If there is no impairment then lymphaticovenular anastomoses (LVA) may be indicated. In this technique, super microsurgery is performed to connect distal subdermal lymphatic vessels to the adjacent venues and thereby improve lymphatic drainage. Three or four bypass anastomoses per patient provide good symptomatic and objective improvements in breast cancer patients. VLNT is an alternative technique which is indicated where there is impairment of flow within the axilla. It involves transfer of vascularized tissue such as the superficial circumflex iliac flap (SCIP flap) containing lymph nodes to the lymphedema limb either distally or proximally. It may be combined with LVA. In patients who have undergone mastectomy, autologous breast reconstruction may be offered. The term “total breast anatomy reconstruction” (TBAR) may be used. This entails abdominal free tissue transfer to reconstruct the breast and incorporates lymph nodes within this flap. In addition, LVA would be incorporated into the surgical procedure.1 Power assisted liposuction has a place in the Barcelona algorithm where there is a nonfunctional lymphatic system. The Miller procedure is not part of the algorithm and involves an excisional approach with a longitudinal medial excision of skin and subcutaneous tissue from the limb. Interposition lymph vessel transplantation was first reported by Baumeister et al in 1986 and involves harvesting two or three ventromedial thigh lymph vessels from the thigh and using these as interposition grafts to bypass a lymphatic obstruction and optimize flow. This procedure is not part of the Barcelona algorithm.2,3 Lymphatic Channels No active lymphatic channels based on imaging Active lymphatic channels based on imaging Treatment: CDT Consider VLNT Treatment: Reductive/Ablative Surgery -Liposuction Pitting Edema Nonpitting Edema Treatment: Physiologic surgery Fig. 69.1 Barcelona lymphedema algorithm for surgical treatment of lymphedema. CDT, complete decongestive therapy; VLNT, vascularized lymph node transfer.