After radical surgeries for cervical, endometrial and ovarian cancers, patients often suffer from chronic leg lymphedema. These patients therefore often suffer leg heaviness, erythema, ulcers and pain, requiring lifelong treatment and psychosocial support [1
]. Such lymphedema is the result of lymphatic system insufficiency and impaired lymph transport due to lymphadenectomy or radiation therapy [2
Ki et al. reported that the incidence of lower-limb lymphedema (LLL) was 11.1% after surgery for ovarian cancer [3
]. In Japan, 16.6% of patients with cervical cancer suffer from LLL after pelvic lymph node removal [4
]. In a prospective longitudinal cohort study (n
= 408), Hayes et al. reported that 50% of patients showed evidence of lymphedema within 2 years post-gynecological cancer, and 60% of lymphedema cases were persistent [5
]. LLL is a common long-term complication that reduces the quality of life (QOL) of gynecological cancer survivors [6
]. Evidence that the disease is often overlooked by physicians caring for such patients lies in the fact that about 60% of patients are self-referred for an initial evaluation after several years [8
]. Therefore, medical teams must address lymphedema as a part of the early treatment of gynecologic cancers.
We herein review the current issues (with a review of the relevant literature) and etiology, symptoms, recent diagnostic procedures and treatments for secondary leg lymphedema in patients with gynecologic cancers and discuss how to better manage leg lymphedema after surgery or radiation therapy.
2. Etiology and Pathophysiology of Leg Lymphedema after Pelvic Lymphadenectomy
Secondary lymphedema is a chronic disease characterized by the accumulation of interstitial fluid in tissues due to damaged lymphatic vessels, leading to leg swelling and dysfunction [10
]. The risk of leg lymphedema has been correlated with the number of lymph nodes removed and the location of the removed lymph nodes. For example, Todo et al. revealed that removal of the circumflex iliac nodes to the distal external iliac nodes (CINDEINs) can be a critical risk factor for postoperative lower-extremity lymphedema [11
]. They also revealed that adjuvant whole pelvic external beam radiation therapy, resection of ≥31 lymph nodes and removal of the CIDENs were significantly related to its occurrence. Similarly, Togami et al. found that the number of lymph nodes removed (odds ration [OR]: 3.37, 95% confidence interval [CI]: 1.43–8.54; p
= 0.0053) and circumflex iliac node (CIN) removal (OR: 3.92; 95% CI: 1.55–11.4; p
= 0.0033) were independent risk factors for lower extremity lymphedema [4
]. In contrast, Hopp et al. suggested that the development of lymphedema may be a process not influenced by the number or location of lymph nodes removed, surgical approach, or medical comorbidities [12
Under normal conditions (before lymphadenectomy), reabsorption of extracellular fluid and protein occurs via both the arteriovenous and the lymphatic capillaries [13
]. An extracellular flow pattern occurs along the connective tissue fiber, and presumably, through prelymphatic channels [14
]. Lymphatic channels primarily regulate the flow of interstitial fluid [15
]. Venous capillaries reabsorb 90% of the interstitial fluid and lymphatic channels absorb the remaining 10% of lymph fluid and proteins [16
]. Fluid and particles enter the initial lymphatics through interendothelial openings and by vesicular transport through the lymphatic endothelial cells [17
]. Intracellular transport occurs through the phagocytosis of macrophages entering the lymphatics.
The main propelling forces for lymph flow are the rhythmic contractions of lymphangions (segments of lymphatics between two unidirectional valves), which generate lymph pressures high enough to move the intralymphatic fluid centripetally [18
]. Muscular contractions, respiratory movements and arterial pulsations play a secondary role to the spontaneous contractions of lymphatics [19
]. Lymphatic contraction can be regulated by the nervous system, as both noradrenergic and sensory nerve endings have been found in the lymphatic wall [13
]. Noradrenaline, serotonin, prostaglandin F2α, thromboxane B2 and endothelin 1 all contract lymph vessels [20
]. Lymphatic fluid then passes to the regional lymph nodes and is transported back into the subclavian vein to enter the venous system via the thoracic duct [22
Pelvic lymphadenectomy or irradiation can induce the destruction or obstruction of the central lymphatic vessels. Leg lymphedema is thus caused by the excess accumulation of tissue fluid and lymph resulting from a lack of proper centripetal drainage due to damage to the lymphatic collector wall [18
]. In other words, endolymphatic pressure increases in the lymphatic vessels of the leg due to the lack of proper centripetal drainage and histological changes in the vessels ensure which causes protein-rich fluid to accumulate in the interstitial spaces of the leg [23
]. Lymphatic capillary hypertension in primary lymphedema has been demonstrated [24
]. Olszewski measured the end pressures of the lymphatic ducts in a lymphedematous human leg during ambulation (up to 200 mmHg) [26
]. A reduced flow or stasis of lymph can result from lymphatic hypoplasia, from the obliteration of lymphatic trunks, from the absence of lymphatic valves, or from impaired lymphatic contractility [27
]. Lymph stasis results in the accumulation of protein in the extracellular space, which increase the tissue colloid osmotic pressure, causing edema formation and the elevation of interstitial hydraulic pressure (Figure 1
]. The potential role of interstitial glycosaminoglycans within the skin and subcutaneous tissue in the pathogenesis of lymphedema has been a point of focus [31
Over time, the inflammatory lymphatic fluid starts to damage the natural lymphatic drainage pathways and surrounding tissue [32
]. The accumulation of proteins attracts macrophages, stimulates collagen production by fibroblasts and enhances the stimulation of fibroblasts, keratinocytes and adipocytes [28
]. In brief, leg lymphedema is a chronic, debilitating condition characterized by the abnormal accumulation of proteinaceous fluid in skin and subcutaneous tissue resulting in subsequent adipose and fibrous tissue hyperplasia [33
In secondary lymphedema, the immune function is significantly compromised. The interaction of CD4+
T cells and macrophages has been shown to play a role in driving the proliferation of lymphatic endothelial cells and aberrant lymphangiogenesis, which contribute to the interstitial fluid accumulation in lymphedema [35
T cells are activated in skin-draining lymph nodes and then migrate to lymphedematous skin [36
]. Activated CD4+
T cells promote fibrosis and inflammation, and inhibit lymphangiogenesis and the lymphatic function.
The clinical severity of the disease symptoms is classified according to the International Society of Lymphology (ISL) and divided into stages 0 to 3 (Table 1
]. A latent or subclinical condition is defined as stage 0. The early accumulation of fluid that subsides with limb elevation is defined as stage 1. The transition from stage 0 lymphedema to stage 1 is defined as the point at which a detectable change in the limb volume occurs [38
]. The condition in which limb elevation alone rarely reduces the tissue swelling and pitting is defined as stage 2. The condition in which the limb may not show any pitting, as excess subcutaneous fat and fibrosis develop, is defined as later stage 2. As the physical properties of the interstitium change during the course of the disease, these changes will alter the hydraulic conductivity of the tissue and thus, both the clearance of fluid and the lymphangiogenic response [39
]. The mechanical changes in the tissue itself (i.e., fibrosis) are a hallmark of disease severity and disease progression to an irreversible state at stage 2 [41
]. The condition in which elephantiasis develops due to alterations in the skin character and thickness is defined as stage 3. Given that inflammatory cytokines have also been shown to affect the collecting lymphatic pump function [43
], it is likely that the consequences of inflammatory-driven lymphedema progression not only alter the interstitium, but severely compromise the pump function and drainage by the collectors at stages 2 and 3 [38
Elephantiasis occurs at stage 3. The main symptom of elephantiasis is gross enlargement and swelling of the legs because of the accumulation of fluid. The entire leg may swell to several times its normal size resembling the thick, round appearance of an elephant’s leg. The skin of the leg usually develops a dry, thickened and pebbly appearance. It presents as diffuse non-pitting edema, ulceration and a hyperkeratotic papulonodule with a verrucous appearance on the leg [45
Cellulitis with lymphangitis sometimes occurs when bacteria or toxin absorbed into wounds or skin infections spread into the subcutaneous tissue of the leg lymphoma [46
]. For example, a 47.6% prevalence rate of cellulitis has been observed among patients in Thailand with lymphedema [47
]. Cellulitis starts with by flu-like symptoms followed by leg erythema and swelling that presents as a hot sensation or tenderness [48
]. Cellulitis is mainly caused β-hemolytic streptococci invasion into the lower extremities [46
Venous capillaries reabsorb 90% of the interstitial fluid and lymphatic channels absorb the remaining 10% of lymph fluid and proteins [16
]. In cases of watery leg edema, such as during pregnancy, the methods of water immersion, bandage and stockings mainly move interstitial fluid from the extravascular space into the venous system [73
], and foot edema can easily be managed. In cases of lymph edema, lymph fluid and protein do not move from the extravascular space into the venous system. Therefore, to treat lymphedema, we must move lymph fluid and proteins into the extravascular space.
Once lymphedema has developed, it has been said that it cannot be cured. Thus, the treatment of lymphedema focuses on reducing the swelling and controlling the pain. In order to reduce the swelling sufficiently, lymphedema must be diagnosed and treatment started as early as possible. We therefore need tools that can help diagnose lymphedema before secondary lymphedema develops. Among the available diagnostic methods, ICG-LG can detect dermal lymph backflow sign in asymptomatic legs and the earliest splash pattern at stage 0 [70
]. Thus, ICG-LG is a considered the most sensitive and useful diagnostic tool for detecting early abnormal lymph flow after the gynecologic surgery.
At symptomatic stage 1, such as during the early accumulation of fluid, a physical examination, ultrasonography, MRI, MRI-LG/CT-LG and lymphosintigraphy are also useful. Of these methods, only a physical examination may not be able to make a quantitative measurement of lymphedema. Ultrasonography, particularly portable ultrasonography, is easy to use and a very convenient tools for checking the degree of lymphedema [51
]. Ultrasonography can easily detect increased skin thickness, increased subcutaneous tissue thickness, and increased subcutaneous echogenicity [52
]. MRI may not be suitable for the diagnosis of changes in lymphedema because water-fat MRI cannot differentiate water signals between fluid and muscle [54
]. Regarding MRI-LG, an intradermal injection rather than a subcutaneous injection is required for the optimal visualization of lymphatics and poor venous contamination [59
]; however, this examination requires a long duration (about an hour). CT-LG enables the clear visualization of lymphatic vessels with a minimum lumen size of 0.7mm [56
] within a short time (about 5 min); however, CT-LG has an undesirable radiation exposure. Lymphoscintigrams of lymphedema show a variety of abnormal lymphatic flow findings [63
], although they cannot detect an abnormal early lymph flow.
To reduce the swelling and control the pain of lymphedema, we basically perform CDP, including MLD, compression therapy, exercise and skin care. These treatments are believed to be the best for managing lymphedema [72
]. Most of the lymphedema volume reduction occurs in the first 10 days of CDP therapy involving MLD [74
]. Because a lower PEV (early stage of lymphedema) can predict a better response to CDP therapy, treatment for lymphedema should be started at the early stage (stages 0–1) in order to reduce lymphedema completely.
Intensive CDP therapy involves MLLB [72
]. Twelve hours per day is a sufficient duration to apply bandaging [78
]. NMLB may also significantly reduce both swelling and swelling-related symptoms [79
]. Newly developed intensive therapy regimens also involve APCDs, which offers several approaches to managing lower extremity swelling, producing a gentle, wave-like application of pressure as the chambers sequentially inflate and deflate [83
]. Of note, the new channels inflate proximally, enabling the moved fluid to be absorbed in areas such as the upper thigh, hip and lumbar region [84
]. The earlier such treatments are started, the better the effect on reducing edema.
LVA procedures for stages 1–2 patients have been developed in recent years. Regarding its indication, this microsurgical procedure may be considered for patients who are refractory to conservative treatment. LVA can be performed if some portions of the peripheral collecting lymphatics remain patent and partially drain tissue edema fluid [92
]. Lymphatic obstruction is more likely with LVEEA than with LVSEA. Therefore, when LVA is performed, LVSEA is principally recommended [95
At stage 2-3, VLNT is useful for lymphedema treatment [100
]. VLNT is thought that transplanted lymph nodes reduce lymphedema by venous shunting and stimulating lymphangiogenesis [100
]. In cases of lymphatic elephantiasis, liposuction or surgical excision is performed to reduce the excess limb volume. LVA and VLNT are said to prevent fluid reaccumulation and reduce the need for compression garment use after liposuction has removed the solid component of the lymphedema [112
]. Regarding surgical excision, the combination of the modified Charles procedure with vascularized transfer of the lymph node flap is effective [115
These ingenious approaches can reduce leg swelling and pain and maintain the QOL of afflicted patients. However, such techniques are limited as treatments because they cannot cure lymphedema completely. Thus, the most important point is preventing the occurrence of secondary lymphedema altogether. After gynecologic cancer surgery or radiation therapy, patients must diligently conduct skin care, weight control, gentle limb exercises, avoidance of the sun and heat and elevation of the affected leg in order to prevent the start of abnormal leg lymph flow [119
]. Furthermore, to prevent lymphedema, the American Cancer Society also suggests that patients ‘Get regular medical check-ups,’ ‘Report any changes to your doctor,’ ‘Try to get and/or stay at a healthy weight,’ ‘Do exercise (Using your muscle also helps the lymph fluid drain like it should,)’ ‘Try to avoid infections, burns, and injuries,’ ‘Try to avoid constriction of the leg,’ ‘Be aware of cellulitis,’ and ‘wear compression garments on long or frequent air travel’ [120
Using preventive methods, we must prevent progression to lymphedema. The above-mentioned risk-reducing behaviors should help to reduce the production of lymph, which is directly proportional to the blood flow, and minimize blockage of lymph transport means [121
]. Sun, heat, infections and injuries increase blood flow and thus lymph production in the leg, while sitting for long periods and compression garments may result in obstruction to lymph flow [121
The duration of the stage 0 (or 1a) period, which refers to a latent or subclinical condition, is thought to be months or years [37
]. The average time from gynecologic cancer treatment to the development of symptomatic lymphedema was reported to be 4.75 years [123
]. After that, the condition progresses to advanced stages over time. Patients and physician need to be aware of this potential long-term iatrogenic complication in order to avoid a delay in the diagnosis and administration of therapy.
Medical teams should be concerned with not only curing gynecologic cancer cures but also preventing and managing side effects as early as possible. We should instruct our teams on preventive methods more carefully and eagerly.