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Lymphoedema in association with skin cancer treatment Dhruvkumar Laheru, Kristiana Gordon This article highlights the underappreciated, debilitating complication of lymphoedema following invasive skin cancer treatment. With increasing rates of skin cancers, it remains imperative that health professionals understand and appreciate this chronic condition and its impact upon patients. Preoperative counselling regarding the risk of lymphoedema and the benefits of early detection should be offered routinely to those undergoing invasive skin cancer treatment. In this paper we highlight the functions of the lymphatic system, the consequences of disruption to lymphatic drainage as a result of skin cancer treatment, and the evaluation of a patient with suspected lymphoedema. The cornerstones of optimal treatment remain good skin care, exercise, manual lymphatic drainage massage and compression therapy. We discuss each in more detail with the aim to provide the reader with a greater understanding of this condition, its complications and how to minimise its impact upon the patient. Laheru D, Gordon K (2016) Lymphoedema in association with skin cancer treatment. Dermatological Nursing 15(1): 14-22

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Introduction

Dr Dhruvkumar Laheru is a Specialist Registrar in Dermatology and Dr Kristiana Gordon is a Consultant Dermatologist at St George’s Hospital, London

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Skin cancer remains the most common form of cancer in the UK (Leigh, 2014). The most prevalent forms of skin cancer comprise the non-melanoma skin cancers (NMSC) — namely basal cell carcinoma (BCC) and squamous cell carcinoma (SCC). Malignant melanoma (MM) accounts for a

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smaller, yet significant, portion of the skin cancer workload. The UK annual incidence of MM is showing a year-onyear increase. More than 13,000 new cases of MM were reported in 2012 in the UK with an incidence rate of 21.1 per 100,000 population (Cancer Research UK, 2016). Treatment modalities for NMSCs are varied, with curative treatments including topical agents, cryosurgery and curettage and excisional surgery. Most cases of NMSC surgery will involve the simple excision of lesional skin with a margin of normal skin to ensure complete removal. However, in cases of MM, it is now common practice to perform a wide local excision (WLE) after initial diagnostic removal. Sentinel lymph node biopsy is offered to many patients with melanoma and a Breslow thickness exceeding 1mm. Similarly, regional lymph node clearance may be offered to patients with skin cancer (MM and NMSC) that has metastasised to regional lymph nodes. Disruption to lymphatic drainage by extensive tissue or lymph node removal may result in lymphoedema. The lymphatics in the skin serve important functions such as immune surveillance, fluid distribution www.bdng.org.uk

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CLINICAL SKILLS and drainage. Any physical destruction of the skin or adjacent subcutaneous tissues may impair the local lymphatic function and has the potential to result in a chronic lymphoedema and increased risk of local immune impairment.

The lymphatic system The lymphatic system comprises an extensive network of lymphatic vessels and lymph nodes distributed throughout the body, draining lymphatic fluid from tissues so that it may enter the cardiovascular system and be filtered from the body. The body’s initial lymphatic vessels within the dermis absorb the interstitial fluid (now called ‘lymph’ when it enters these vessels) that has been filtered from the capillary beds of peripheral tissues. Lymphatic fluid is actively pumped through a complex network of lymph vessels and nodes, back into the central venous vessels via the thoracic duct, in order to mix with the blood prior to being re-circulated by the heart. The lymphatic system plays a pivotal role in protein, fluid and fat homeostasis, aiding cellular drainage from tissues (Figures 1a and 1b). The lymphatic system also plays a crucial role in immune surveillance, as it is responsible for the early detection of invading pathogens (via breaches in the epidermis) and in instigating an immune response to eradicate infection before it can harm the individual (Mortimer, Rockson, 2014). An accumulation of interstitial fluid may occur at any site when capillary microvascular filtration exceeds lymphatic drainage capacity. It is called lymphoedema when this results in swelling visible to the patient or clinician. This may occur as a result of a primary lymphoedema where the patient has a congenital genetically determined lymphatic impairment (Connell et al, 2013), or as a result of lymphatic impairment from physical damage to the lymphatic system (secondary lymphoedema). Numerous causes of secondary lymphoedema exist, including venous hypertension, chronic inflammatory conditions (eg, acne, rosacea, eczema or psoriasis) but www.bdng.org.uk

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Jugular lymphatic trunk Internal jugular v. Right lymphatic duct (Venous angle)

Cervical lymph nodes Arch of thoracic duct Cervical part

Subclavian v. Subclavian lymphatic trunk Bronchomediastinal lymphatic trunk

Thoracic part

Axillary lymph nodes

Thoracic duct

Abdominal part Cistema chyli Intestinal trunks

Abdominal lymph nodes, parietal and visceral Pelvic lymph nodes, parietal and visceral

Lumbar trunks

Inguinal lymphatic nodes Lymphatic vessels

Figure 1a The lymphatic system comprises a widespread network of lymphatic vessels and lymph nodes. cancer treatment modalities such as lymph node dissection and radiotherapy are a frequent cause of lymphoedema (Moffatt et al, 2003).

Venous system

Lymph duct

Lymphoedema as a result of skin cancer treatment Skin cancer treatment may result in the physical disruption of lymphatic drainage pathways of tissues. In dermatological surgery the complications of infection, bleeding, scarring, neurovascular damage and tumour recurrence are often cited. However, few patients are aware of the risk of post-operative swelling/ lymphoedema. The cutting of skin, in all but the trivial forms, is likely to disrupt small (and possibly even the larger) lymphatic vessels within the dermis. However, simple excision of lesions, curettage or aggressive cryotherapy are unlikely to cause lymphoedema unless the patient has an underlying primary lymphoedema (a rare genetically determined weakness of the lymphatic system that may be sub-clinical at the time of their skin cancer presentation) which renders them highly susceptible to

Arterial system

Heart Lymph trunk Lymph node

Lymphatic system Lymphatic collecting vessels, with valves Lymph capillary

Blood capillaries

Tissue fluid (becomes lymph)

Loose connective tissue around capillaries

Figure 1b The lymphatic system is responsible for fluid homeostasis. Interstitial fluid is absorbed by lymphatic vessels and transported via a unidirectional network to the cardiovascular system.

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CLINICAL SKILLS lymphoedema in the setting of minimal skin/soft tissue trauma. Patients undergoing larger resections and surgery at certain sites are at higher risk of lymphoedema. For example, surgery affecting the axillae and groins (where the draining collector vessels and lymph nodes are relatively superficial, thus more vulnerable to surgical trauma) may be considered ‘at risk’ sites. It has also been shown that melanoma thickness (>4mm), graft reconstruction, lymphadenectomy, post-operative seroma (localised collection of lymphatic fluid as a result of lymphatic vessel damage) and post-operative infection are all risk factors for lymphoedema development (Campanholi et al, 2011). Severe cellulitis is associated with a significant inflammatory response, which has the potential to cause damage to lymphatic vessels and can result in chronic lymphoedema (Mortimer, Rockson, 2014). Surgical skin cancer management involving sentinel lymph node biopsy, lymph node clearance or aggressive radiotherapy are treatment modalities with a high risk of causing lymphatic destruction and potential to cause lymphoedema (Figure 2). Lymphoedema secondary to skin cancer treatment has not been widely studied but we can look to the medical literature on lymphoedema resulting from other malignancies and their treatment as some data could be transferable to the skin cancer patient cohort. For example, upper limb lymphoedema is a well-studied complication of breast cancer treatment with an estimated occurrence of 22.3% (range: 11-57%) in patients undergoing axillary lymph node dissection (Shaitelman 2015). Patients undergoing adjuvant radiotherapy have a higher risk of developing lymphoedema (Ozaslan, 2004). Breast cancer patients are routinely counselled regarding the risks of lymphoedema prior to undergoing axillary lymph node removal. Professionals involved in the management of skin cancer are probably less aware of the risk of 16

lymphoedema following aggressive treatment. However, publications are now emerging of lymphoedema associated with melanoma and/or its treatment; reportedly affecting 10%-40% of patients undergoing nodal dissection (Rockson 2008, Cromwell 2015). Friedman et al (2015) recently published a prospective study in 310 patients with MM, looking at the incidence of lymphoedema following lymph node dissection. The overall incidence of postoperative lymphoedema in their cohort was 20.8%. The incidence of upper limb lymphoedema following axillary lymph node dissection (ALND) was 9.3%, while the incidence of lower limb lymphoedema following inguinal lymph node removal (ILND) was much higher at 32.8%. The incidence of lymphoedema could not be correlated to the number of lymph nodes removed nor the number of excised nodes positive for metastatic disease (Friedman et al, 2015). The finding of ILND exhibiting a higher risk of lymphoedema compared to ALND is widely reported in the literature. An extensive review of the literature by Shaitelman et al (2015) concluded that the incidence of lymphoedema following ALND for MM was 9.9% (range 1-39%) and for ILND was 31.4% (range 6-61%). The risk of developing lymphoedema after sentinel lymph node biopsy (rather than nodal clearance) is lower, with an average incidence of 4.1% (Shaitelman et al, 2015). Nonetheless, patients should be consented about the potential risk of lymphoedema for both procedures. Unfortunately, there is minimal data on the incidence of lymphoedema following lymph node removal for the treatment of NMSC (presumably due to a smaller caseload), but it would seem probable that lymph node clearance for NMSC and MM confers a similar risk of postoperative lymphoedema, and patients should be counselled accordingly. It is not only surgical disruption that damages the lymphatics, but radiation may cause it too. Radiotherapy may be offered to patients with skin cancer either as a palliative or curative strategy. It too has the potential for lymphatic disruption and resultant lymphoedema. Few lymphoedema studies have

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Figure 2 Right lower limb lymphoedema following surgical excision of a melanoma (from the right medial calf) and subsequent inguinal lymph node dissection. included detailed descriptions of radiation treatment targets, rendering it challenging to separate the effects of radiation from those of surgery on lymphoedema development, but it can be concluded that radiation therapy is an independent risk factor for the development of lymphoedema (Hinrichs et al, 2004). Post-operative infections are not only a risk factor for the development of lymphoedema, but a consequence of it too. Every inflammatory/infective episode serves to further disrupt the lymphatic system’s ability to drain and immunoregulate the region, thereby creating a vicious cycle of events that can lead to recurrent cellulitis and recalcitrant lymphoedema.

Complications of lymphatic disruption Disruption of this fine, extensive network of lymphatic vessels and lymph nodes results in complications inextricably linked to its varied functions. Accumulation of lymphatic fluid leads to the clinical condition of lymphoedema, resulting in elephantiasis skin changes if poorly managed, ie, progressive www.bdng.org.uk

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Figure 3 Figure 4

Skin changes associated with chronic left lower limb lymphoedema: hyperkeratosis, papillomatosis and a few lymphangiectasia.

Severe right lower limb cellulitis on a background of lower limb secondary lymphoedema (resulting from inguinal lymph node removal).

swelling of a limb/region, papillomatosis, hyperkeratosis and lymphangiectasia (small ‘lymph blisters’ that frequently leak lymphatic fluid) (Figure 3). Chronic lymphorrhoea (leakage of lymphatic fluid) will result in a regional irritant dermatitis with possible progression to ulceration if not managed promptly with adequate compression, emollients and topical steroids.

Figure 5

Reduced immune surveillance, as a result of impaired lymphatic drainage, leads to increased propensity of infections. The lymphatic system plays a key role in patrolling the tissues for invasion by pathogens and setting up the appropriate immune response. Resulting infections may be bacterial (commonly cellulitis), viral (eg, warts) and fungal infections (eg, tinea pedis). These complications may lead to further infections, for example the development of interdigital fissuring from tinea pedis will permit the entry of bacteria and result in cellulitis and subsequent lymphatic destruction — perpetuating the infection-inflammation-lymphatic destruction cycle (Figure 4). Once a patient with lymphoedema has suffered from cellulitis, it is not uncommon for them to develop recurrent cellulitis of the same site. Repeated infections 18

Lymphangiosarcoma arising within chronic lymphoedema. may present in an atypical fashion with minimal skin changes and/or no rise in inflammatory markers, often leading to inappropriate discharge without antibiotics from GPs and A&E departments. The key to detecting this low-grade form of ‘grumbling cellulitis’ is to elicit a history of flu-like symptoms and discomfort in the affected limb. It may be prudent to recommend long-term antibiotic prophylaxis for recurrent cellulitis to combat the cycle of repeated infections (and consequent exacerbation of lymphoedema) if the patient has more than two episodes of cellulitis per year (Oh et al, 2014). The BLS has developed a set of management guidelines to aid healthcare professionals involved with these complex patients — please see resource box at the end of this article for some useful websites.

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Aside from infection, the reduced immune surveillance from lymphatic disruption may rarely lead to a cutaneous malignancy within the lymphoedematous region. Patients with chronic lymphoedema (primary or secondary) have a small, yet significant, risk of developing NMSC, MM and lymphangiosarcoma (the so-called ‘Stewart-Treves syndrome’) within the affected region (Benson et al, 1988; Epstein, Mendelsohn, 1984; Bartal, Pinski, 1985; Stewart, Treves, 1948). Clinicians should bear this in mind and ensure that non-healing or progressive ulceration on a background of chronic lymphoedema is investigated to exclude a malignancy (Figure 5). Clinicians should be aware that recurrence of the patient’s primary www.bdng.org.uk

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CLINICAL SKILLS malignancy may present with the development of lymphoedema, or more commonly with a deterioration in preexisting lymphoedema. Investigations to exclude cancer recurrence should be considered in patients with progressive lymphoedema in the absence of other causes (ie, recurrent infection or poor compliance with treatment). The increased weight and dimensions of the lymphoedematous body part can cause musculoskeletal complications such as back pain, joint issues and balance problems. The psychological impact of lymphoedema can be devastating and should not be ignored. It results in altered body image, loss of function and independence and the long-term fear of these struggles with no clear end-point for many (Thomas, Hamilton, 2014). Lymphoedema therapists are trained to detect these complications and can facilitate referral to other specialists who assist with management.

minute: lymphoedema is confirmed when removal of your thumb leaves a clear indentation, ie the oedema is ‘pitting’. Chronic lymphoedema can result in gross swelling of the affected area (assuming it has not been managed prior to the consultation), discomfort, a brawny texture to the skin, hyperkeratosis, prominent skin creases, papillomatosis and lymphorrhoea. If a patient has been counselled in the preoperative period regarding risks of developing lymphoedema then they may be the ones to raise the issue with

Clinical assessment and investigations Initial clinical assessment of a patient with suspected lymphoedema should comprise a full history and examination. Note the extent of the skin cancer surgery performed, adjuvant treatments (eg, radiotherapy), post-operative complications (eg, seroma development following lymph node removal; post-operative cellulitis causing further lymphatic damage) and the time course of the symptom onset in order to determine if skin cancer treatment is the cause of their lymphoedema. It is also important to note the patient’s current disease status as lymphoedema can be challenging to manage in the presence of active metastatic malignancy within the lymphatic system/lymph nodes (as cancer cells cause a physical obstruction to lymphatic fluid passage through the small vessels and nodes).

Figure 6(a) shows normal lower limb lymphoscintigraphy as evidenced by symmetrical uptake of tracer within the main lymphatic vessels of the legs. The tracer has reached both inguinal lymph node regions following injection in the feet 2 hours previously. Figure 6(b) demonstrates normal lymphatic drainage in the patient’s left leg. The right leg shows abnormal lymphatic drainage with re-routing of dye tracer within the superficial lymphatic vessels as it attempts to bypass obstruction to lymphatic drainage around the groin as a result of inguinal lymph node dissection for melanoma treatment.

Clinical signs of lymphoedema will be dependent on the time course. The earliest of stages may solely comprise localised or distal swelling to the operation site. This can be demonstrated by pressing your thumb firmly over the swollen region for one

Early diagnosis is important as it should facilitate access to lymphoedema treatment, preventing disease progression and reducing the risk of complications. There are no data to support the prophylactic use of compression garments in order to

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Figure 6

their skin cancer specialist. The patient may complain of tight jewellery/watch strap on an affected upper limb, or tight footwear/’sock marks’ on a lower limb.

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prevent development of lymphoedema after lymph node removal, but further studies are currently underway to evaluate this in greater detail (Stuiver et al, 2013). Diagnosis of lymphoedema remains clinical, but includes consideration and elimination of other differentials. These include: an acute deep vein thrombosis, localised musculoskeletal disorders (eg, Baker’s cyst as a cause of belowknee swelling), dependency oedema, congestive cardiac failure and druginduced causes (eg, calcium channel blockers) to name a few (Toland et al, 2000). Investigations will be guided by assessment of each case and are not necessary for all patients. Ultrasound Doppler and duplex studies can be helpful in evaluating venous anomalies. Cross-sectional imaging (computed tomography or magnetic resonance imaging) may be helpful when searching for deep-seated lymphatic obstruction such as a tumour. The most widely available investigation for confirmation of lymphatic insufficiency (used when the diagnosis of lymphoedema may be uncertain) is lymphoscintigraphy. This involves the injection of a radiolabelled isotope colloid, exclusively cleared by the lymphatics, injected into the dermis and its uptake through the lymphatic drainage routes of a limb is charted over time (Figure 6). Lymphoscintigraphy results can provide a quantified assessment of lymphatic drainage function but cannot provide anatomical or clear functional information. It is likely that MR lymphangiography will yield more useful data on the structure and function of the lymphatic system, but this investigation is currently only available as a research tool within the UK. Other imaging modalities include indocyanine green fluorescence lymphangiography (ICG) where the superficial lymphatic vessels are visualised in vivo in patients being considered for lymphaticovenular anastomosis surgical management.

Management of lymphoedema Lymphoedema used to be considered an irreversible progressive condition www.bdng.org.uk

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CLINICAL SKILLS with little or no treatment potential. In reality, treatment is possible with significant potential for improvements in symptoms and quality of life. However, treatment success relies heavily on the patient’s motivation and compliance with management strategies. The cornerstones of lymphoedema management centre on the principle of getting the most out of the patient’s remaining lymphatic drainage function via good skin care, exercise, massage and compression. Good skin care with attention to hygiene helps reduce the hyperkeratosis and reduce the bacterial burden of the surface layer. Adequate washing, drying and moisturising are essential to maintain the delicate skin barrier function. Infections must be treated promptly and adequately, including regular surveillance and eradiation of interdigital tinea pedis (to prevent fissuring and subsequent bacterial entry). Prophylactic antibiotics should be considered in all patients with recurrent cellulitis. Massage therapy, more formally known as manual lymphatic drainage (MLD), uses gentle pressures and slow movements to relocate lymphatic fluid back to the more central and collateral routes. A variety of techniques is employed by MLD therapists, all with similar outcomes. MLD alone will not have a significant impact on a patient’s lymphoedema unless combined with some form of compression, as the results are short-lived (Lymphoedema Framework, 2006). MLD can also

be performed by nurses (and other healthcare professionals) who have been trained in this specialist massage technique. External compression complements the exercise regime rather than being a substitute. The exogenous force also serves as resistance to excessive capillary interstitial fluid filtration. Compression may take the form of multi-layer lymphoedema bandaging but this is typically reserved for the initial management of significantly swollen limbs. Daily bandaging, in combination with manual lymphatic drainage massage and exercise, can achieve a rapid reduction in limb volumes. The bandages are inelastic and provide a rigid casing for the muscle pump action to work against (Figure 7). The aim is to reduce the limb/body area’s size and restore shape, allowing for fitting of compression hosiery to maintain the reduced limb volume size in the future. Use of compression bandaging is not necessary in the management of mild lymphoedema as good results can be achieved with the daily use of a compression garment (eg, sleeve for upper limb swelling, or socks/tights for lower limb lymphoedema). Compression hosiery comes in a variety of forms. The severity of lymphoedema will determine the class/grade required to keep the swelling under control. Garments are suitable for most patients but arterial insufficiency, severe peripheral neuropathy and skin ulceration may preclude their use. Patients need to be motivated and understand that daily

use is necessary (they do not need to be worn at night) in order to maintain long-term limb volume reduction. Good dexterity or assistance at home are necessary factors in order to ensure compliance. New and improved compression tools are in constant development and now include velcrostyle garments to assist patients with poor dexterity or complex medical problems that preclude the use of standard compression garments. Garments need to be cared for in order to maintain their compression ability. Patients are entitled to two new sets of garments every six months on prescription in the UK. Exercise and movement are key to stimulating existing lymphatic drainage. The effects are enhanced if exercise is undertaken while in compression hosiery (except for swimming as the water forces mimic the pressure from garments) as the forces/pressure from muscle contractions work against the garment pressure to force the lymphatic fluid to drain proximally. An additional role of the lymphoedema nurse (and a specialist skin cancer nurse with an interest in lymphatic disorders) is to provide support and guidance to the patient as they come to terms with the diagnosis of lymphoedema. Lymphoedema is a chronic incurable condition that has the potential to cause psychological morbidity. Patients will benefit greatly from the opportunity to discuss the impact that their condition has upon their quality of life with an interested healthcare professional. They will also significantly benefit if their nurse is able to provide guidance on managing a chronic disease, eg recommending their GP refer for psychological support or suggesting they become members of the Lymphoedema Support Network (so they can access information on numerous issues such as travel precautions, etc).

Other lymphoedema treatment options Figure 7 Multi-layer compression bandaging of the lower limb. www.bdng.org.uk

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Longstanding lymphoedema of a limb may occasionally turn ‘fatty’, ie the fluid component is replaced by adipose tissue. The reasons Dermatological Nursing 2016 Vol 15 No 1

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CLINICAL SKILLS for this phenomenon are not yet fully understood but may relate to the lymphatic system’s role in fat homeostasis within the body. In this situation, the increased limb volumes will not respond to conventional lymphoedema therapy, as compression cannot augment the adipocytes. Patients can be considered for liposuction surgery to debulk an affected limb, but it should be undertaken by experts within the field in order to reduce the postoperative complications (Damstra et al, 2009). Patients must comply with wearing compression garments (day and night) for life to prevent the limb ‘re-filling’ with lymphoedema fluid after the invasive procedure. Surgical methods trialled in lymphoedema management include lymphaticovenous anastomosis surgery (where small lymphatic vessels are anastomosed to nearby veins in an attempt to bypass obstruction to lymphatic flow) or lymph node transfer procedures. Discussion of these treatment options is outside the scope of this article, but the current literature suggests there is a need to improve outcomes before surgery can be recommended for the majority of patients (Hadamitzky et al, 2014).

Specialist lymphoedema access Lymphoedema treatment and provision will vary across the UK, but dedicated lymphoedema clinics have been established to provide care in all regions of the country. The majority of clinics are led by specialist nurses or physiotherapists, and a few will have the support of a local physician to advise on complications such as recurrent cellulitis. Patients can be referred to their regional lymphoedema service by their GP. A directory of UK clinics can be located via the BLS website (see Resources below). Physician-led tertiary referral centres provide support for the management of more complex cases, including patients that fail to respond to standard treatment regimes. These clinics are based at St George’s Hospital in London and the Royal Derby DN Hospital, Derby. 22

Acknowledgements All images used with patients’ permission.

Hadamitzky C, Pabst R, Gordon K, Vogt P (2014) Surgical procedures in lymphedema management. J Vasc Surg 2(4): 461-468 Hinrichs CS, Watroba NL, Rezaishiraz H, Giese W, Hurd T, Fassl KA, Edge SB (2004) Lymphedema secondary to postmastectomy radiation: incidence and risk factors. Ann Surg Oncol 11(6): 573-580 Leigh IM (2014) Progress in skin cancer: the UK experience. Br J Dermatol 171(3): 443-445 Lymphoedema Framework (2006) Best Practice for the Management of Lymphoedema: International Consensus. MEP Ltd, London

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Moffatt CJ, Franks PJ, Doherty DC, Williams AF, Badger C, Jeffs E, et al (2003) Lymphoedema: an underestimated health problem. QJM 96(10): 731-738 Mortimer P, Rockson S (2014) New developments in clinical aspects of lymphatic disease. J Clin Invest 124(3): 91521 Oh CC, Ko HC, Lee HY, Safdar N, Maki DG, Chlebicki MP (2014) Antibiotic prophylaxis for preventing recurrent cellulitis: a systematic review and meta-analysis. J Infect 69(1): 26-34 Ozaslan C, Kuru B (2004) Lymphedema after treatment of breast cancer. Am J Surg 187(1): 69-72 Rockson SG, Rivera KK (2008) Estimating the population burden of lymphedema. Ann New York Acad Sci 1131: 147-54 Shaitelman SF, Cromwell KD, Rasmussen JC, Stout NL, Armer JM, Lasinski BB, Cormier JN (2015) Recent progress in the treatment and prevention of cancer-related lymphedema. CA Cancer J Clin 65(1): 55-81 Stewart FW, Treves N (1948) Lymphangiosarcoma in postmastectomy lymphoedema. Cancer 1(1): 64-81 Stuiver MM, de Rooij JD, Lucas C, Nieweg OE, Horenblas S, van Geel AN, et al (2013) No evidence of benefit from class-II compression stockings in the prevention of lower-limb lymphedema after inguinal lymph node dissection: results of a randomized controlled trial. Lymphology 46(3): 120-31

Damstra RJ, Voesten HG, Klinkert P, Brorson H (2009) Circumferential suction-assisted lipectomy for lymphoedema after surgery for breast cancer. Br J Surg 96(8): 859-864

Thomas R, Hamilton R (2014) Illustrating the (in)visible: understanding the impact of loss in adults living with secondary lymphedema after cancer. Int J Qual Stud Health Well-being 9: 24354

Epstein JL, Mendelsohn G (1984) Squamous carcinoma of the foot arising in association with longstanding verrucous hyperplasia in a patient with congenital lymphoedema. Cancer 54(5): 943-7

Toland HM, McCloskey KD, Thornbury KD, McHale NG, Hollywood MA (2000) Ca(2+)-activated Cl(–) current in sheep lymphatic smooth muscle. Am J Physiol Cell Physiol 279(5): C1327-C1335

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Friedman JF, Sunkara B, Jehnsen JS, Durham A, Johnson T, Cohen MS (2015) Risk factors associated with lymphedema after lymph node dissection in melanoma patients. Am J Surg 210(6): 1178-1184

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