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Department of Plastic Surgery, Tokyo Metropolitan Bokutoh Hospital, Tokyo, JapanDepartment of Plastic and Reconstructive Surgery, The University of Tokyo, Tokyo, Japan
Indocyanine green (ICG) lymphography has been reported to be useful for the early diagnosis of lymphoedema. However, no study has reported the usefulness of ICG lymphography for evaluation of lymphoedema with lower extremity dysmorphia (LED). This study aimed to elucidate independent factors associated with LED in secondary lower extremity lymphoedema (LEL) patients.
Methods
This was a retrospective observational study of 268 legs of 134 secondary LEL patients. The medical charts were reviewed to obtain data of clinical demographics and ICG lymphography based severity stage (leg dermal backflow [LDB] stage). LED was defined as a leg with a LEL index of 250 or higher. Logistic regression analysis was used to identify independent factors associated with LED.
Results
LED was observed in 106 legs (39.6%). Multivariate analysis revealed that independent factors associated with LED were higher LDB stages compared with LDB stage 0 (LDB stage III; OR 17.586; 95% CI 2.055–150.482; p = .009) (LDB stage IV; OR 76.794; 95% CI 8.132–725.199; p < .001) (LDB stage V; OR 47.423; 95% CI 3.704–607.192; p = .003). On the other hand, inverse associations were observed in higher age (65 years or older; OR 0.409; 95% CI 0.190–0.881; p = .022) and higher body mass index (25 kg/m2 or higher; OR 0.408; 95% CI 0.176–0.946; p = .037).
Conclusions
Independent factors associated with LED were elucidated. ICG lymphography based severity stage showed the strongest association with LED, and was useful for evaluation of progressed LEL with LED.
This is the first report that has clarified independent factors associated with lower extremity dysmorphia (LED). Indocyanine green (ICG) lymphography based leg dermal backflow (LDB) stage has the strongest association with LED, and is useful for evaluation of late stage lymphoedema with LED. Patients with higher LDB stage should be carefully followed with consideration of aggressive treatment to prevent lymphoedema progression.
Introduction
Lymphoedema is a debilitating oedematous disease. With the increasing number of cancer survivors, cancer related lymphoedema is becoming a major public health issue.
Overview of treatment options and review of the current role and use of compression garments, intermittent pumps, and exercise in the management of lymphedema.
In particular, lower extremity lymphoedema (LEL) patients are likely to suffer from refractory lymphoedema, because the lower extremities are directly affected by gravitational effects during standing and walking. The lower extremity becomes dysmorphic with progression of LEL, which causes significant cosmetic and functional problems.
Overview of treatment options and review of the current role and use of compression garments, intermittent pumps, and exercise in the management of lymphedema.
For better management of LEL, it is important for medical staff to be aware of the factors associated with lower extremity dysmorphia (LED), which is commonly seen in progressed LEL cases.
Practicality of lower extremity lymphedema index: lymphedema index versus volumetry-based evaluations for body-type corrected lower extremity volume evaluation.
Indocyanine green (ICG) lymphography clearly visualises superficial lymph flow in real time without radiation exposure, and has been applied in the evaluation of lymphoedema.
Severity staging systems based on ICG lymphography findings have been developed for evaluation of arm, leg, genital, and facial lymphoedema, and are reported to be useful for the early diagnosis of obstructive lymphoedema.
Characteristic indocyanine green lymphography findings in lower extremity lymphedema: the generation of a novel lymphedema severity staging system using dermal backflow patterns.
The earliest finding of indocyanine green lymphography in asymptomatic limbs of lower extremity lymphedema patients secondary to cancer treatment: the modified dermal backflow stage and concept of subclinical lymphedema.
ICG lymphography has become one of the most important pre-operative lymphoedema assessments, and plays an important role as an intra-operative navigation tool.
Navigation lymphatic supermicrosurgery for iatrogenic lymphorrhea: supermicrosurgical lymphaticolymphatic anastomosis and lymphaticovenular anastomosis under indocyanine green lymphography navigation.
Although several reports have shown the usefulness of ICG lymphography for lymphoedema evaluation in the early stages of LEL and intra-operative navigation, no study has reported on the usefulness of ICG lymphography for evaluation of progressed LEL with LED.
Characteristic indocyanine green lymphography findings in lower extremity lymphedema: the generation of a novel lymphedema severity staging system using dermal backflow patterns.
The earliest finding of indocyanine green lymphography in asymptomatic limbs of lower extremity lymphedema patients secondary to cancer treatment: the modified dermal backflow stage and concept of subclinical lymphedema.
Navigation lymphatic supermicrosurgery for iatrogenic lymphorrhea: supermicrosurgical lymphaticolymphatic anastomosis and lymphaticovenular anastomosis under indocyanine green lymphography navigation.
Since LED is associated with cosmetic and functional morbidity and should be prevented, LED associated factors should be clarified. This study aimed to elucidate independent factors associated with LED.
Materials and Methods
Two hundred and sixty eight limbs of 134 female patients with LEL secondary to pelvic cancer treatments who underwent bilateral pedal ICG lymphography between June 2009 and August 2014, under ethics committee approved protocol, were included in this study. All patients suffered from progressive lymphoedema secondary to pelvic lymphadenectomy refractory to compression therapy. No patient had past history of lymphoedema surgery. Clinical charts were reviewed to collect clinical and ICG lymphography findings; clinical findings when ICG lymphography was performed were used for analysis.
Recorded clinical findings included age, body mass index (BMI), duration of oedema, past history of radiotherapy, past history of cellulitis, and limb circumferences. Duration of oedema was defined as time from symptomatic oedema onset to appointment for physical examination. Circumferences were measured at and 10 cm above and below the superior edge of the patella (C1, C2, C3), at the superior edge of the lateral malleolus (C4), and at the midpoint of the first metatarsal (C5). LEL index, index for body type corrected lymphoedematous lower extremity volume evaluation, was calculated based on the following formula; LEL index=(C12 + C22 + C32 + C42 + C52)/BMI.
Practicality of lower extremity lymphedema index: lymphedema index versus volumetry-based evaluations for body-type corrected lower extremity volume evaluation.
Unlike conventional volume measurement, LEL index is less influenced by body physique, and allows direct limb comparison between patients with different body physiques.
Practicality of lower extremity lymphedema index: lymphedema index versus volumetry-based evaluations for body-type corrected lower extremity volume evaluation.
Characteristic indocyanine green lymphography findings in lower extremity lymphedema: the generation of a novel lymphedema severity staging system using dermal backflow patterns.
The earliest finding of indocyanine green lymphography in asymptomatic limbs of lower extremity lymphedema patients secondary to cancer treatment: the modified dermal backflow stage and concept of subclinical lymphedema.
: 0.2 mL of ICG (Diagnogreen 0.25%; Daiichi Pharmaceutical, Tokyo, Japan) was injected subcutaneously in the first web space and the lateral border of the Achilles tendons in both feet. After ICG injection, circumferential fluorescent images of lymphatic drainage channels were obtained using an infrared camera system (Photodynamic Eye [PDE]; Hamamatsu Photonics K.K., Hamamatsu, Japan). ICG lymphographic images were recorded at a plateau phase of the lymphography (12–18 h after injection). Based on ICG lymphography findings, leg dermal backflow (LDB) stage was determined as previously reported (Table 1 and Figure 1, Figure 2, Figure 3, Figure 4, Figure 5, Figure 6, Figure 7).
The earliest finding of indocyanine green lymphography in asymptomatic limbs of lower extremity lymphedema patients secondary to cancer treatment: the modified dermal backflow stage and concept of subclinical lymphedema.
Figure 1Indocyanine green (ICG) lymphography findings. With progression of lymphoedema, ICG lymphography finding changes from Linear pattern (left), to Splash pattern (centre left), to Stardust pattern (centre right), and finally to Diffuse pattern (right).
Figure 5Leg dermal backflow stage III. Stardust pattern is seen in the thigh and lower leg on indocyanine green lymphography. Linear pattern is also seen.
Figure 6Leg dermal backflow stage IV. Stardust pattern is seen in the thigh, lower leg, and foot on indocyanine green lymphography. Linear pattern is also seen.
Figure 7Leg dermal backflow stage V. Diffuse or Stardust pattern is seen in a whole limb including the thigh, lower leg, and foot on indocyanine green lymphography. Linear pattern is not seen.
LED was defined as a limb with a LEL index of 250 or higher, and set as a dependent variable. LEL index of 250 was reported to be a borderline of normal limb and significantly enlarged lymphoedematous limb according to previous studies.
Practicality of lower extremity lymphedema index: lymphedema index versus volumetry-based evaluations for body-type corrected lower extremity volume evaluation.
Independent variables included age (<65 years vs. 65 + years), BMI (<25 kg/m2 vs. 25 + kg/m2), duration of oedema (<60 months vs. 60 + months), past history of radiation (positive vs. negative), past history of leg cellulitis (positive vs. negative), and LDB stage (stage 0 vs. stage I/II/III/IV/V).
Univariate analyses were done using chi-square test and Fisher exact probability test; chi-square test was used where all expected values were 5 or higher, whereas Fisher exact probability test was used where at least one of the expected values was lower than 5. Multivariate analysis was done using multiple logistic regression analysis. Statistical significance was defined as p < .05. All patients gave written consent to this study.
Results
Patient age ranged from 36 to 81 years (median 55 years), BMI from 16.2 to 33.3 kg/m2 (median 22.4 kg/m2), and duration of oedema from 3 to 324 months (median 48 months). Forty-eight patients (35.8%) had past history of radiation, and 76 patients (56.7%) had past history of cellulitis. LDB stage included stage 0 in 11 limbs (4.1%), stage I in 62 limbs (23.1%), stage II in 56 limbs (20.9%), stage III in 75 limbs (28.0%), stage IV in 53 limbs (19.8%), and stage V in 11 limbs (4.1%). LED was observed in 106 limbs (39.6%).
Univariate analysis revealed significant differences in the LED rate between negative and positive past history of cellulitis (30.1% vs. 46.4%, p = .006), and between LDB stage 0 and LDB stage III/IV/V (9.1% vs. 56.0%/81.1%/72.7%, p = .004/<.001/.002) (Table 2 and Fig. 8).
Table 2Univariate analysis of LED associated factors.
Multivariate analysis revealed that independent factors associated with LED were higher LDB stages compared with LDB stage 0 (LDB stage III; OR 17.586; 95% CI 2.055–150.482; p = .009) (LDB stage IV; OR 76.794; 95% CI 8.132–725.199; p < .001) (LDB stage V; OR 47.423; 95% CI 3.704–607.192; p = .003). On the other hand, inverse associations were observed in higher age (age 65 years or older; OR 0.409; 95% CI 0.190–0.881; p = .022) and higher BMI (BMI of 25 kg/m2 or larger; OR 0.408; 95% CI 0.176–0.946; p = .037) (Table 3).
Table 3Multivariate analysis of LED associated factors.
Previous studies have reported potential factors associated with LEL severity, which were included and evaluated in this study to confirm LED associated factors by multivariate analysis.
Overview of treatment options and review of the current role and use of compression garments, intermittent pumps, and exercise in the management of lymphedema.
In progressed LEL cases, morphological changes of lymphoedematous limbs are common, which should be prevented by appropriate management. Although swelling or pitting oedema is a common feature in LEL, morphological changes are caused not only by pitting oedema caused by lymph retention but also by non-pitting oedema caused by fat deposition. Therefore, the term “LED” has been used to represent the morphological changes of lymphoedematous limbs, as the term “swelling” seemed inappropriate.
Practicality of lower extremity lymphedema index: lymphedema index versus volumetry-based evaluations for body-type corrected lower extremity volume evaluation.
The earliest finding of indocyanine green lymphography in asymptomatic limbs of lower extremity lymphedema patients secondary to cancer treatment: the modified dermal backflow stage and concept of subclinical lymphedema.
The present study revealed that higher LDB stage, lower age, and lower BMI were LED associated factors. Among them, LDB stage had the highest OR, and was considered the most important factor for LED. Contrary to some previous reports,
Overview of treatment options and review of the current role and use of compression garments, intermittent pumps, and exercise in the management of lymphedema.
lower BMI was associated with LED. As LED was defined using LEL index which was a BMI corrected lymphoedematous volume, a patient with lower BMI would be likely to have higher LEL index and to be associated with LED.
LED is associated with significant clinical problems in physical appearance and function, and has a significant detrimental impact on LEL patients' quality of life.
Overview of treatment options and review of the current role and use of compression garments, intermittent pumps, and exercise in the management of lymphedema.
Practicality of lower extremity lymphedema index: lymphedema index versus volumetry-based evaluations for body-type corrected lower extremity volume evaluation.
The earliest finding of indocyanine green lymphography in asymptomatic limbs of lower extremity lymphedema patients secondary to cancer treatment: the modified dermal backflow stage and concept of subclinical lymphedema.
As revealed in this study, it is important for medical staff who care for lymphoedema patients to be aware of LED associated factors. Although commonly applied in clinical situations, volume measurement is inappropriate or even impossible to evaluate LED, because volume difference is not adequate for evaluation in most LEL cases especially with bilateral involvement; “normal” limb volume cannot be determined in bilateral LEL patients, and volume does not give information on how much an affected limb has increased in size. In addition, a given volume difference has different clinical impact on patients with different body physiques; for example, 500 mL increase in a limb of a patient with BMI of 20 kg/m2 should mean more severe lymphoedematous change than that of a patient with BMI of 40 kg/m2.
Practicality of lower extremity lymphedema index: lymphedema index versus volumetry-based evaluations for body-type corrected lower extremity volume evaluation.
Concurrent validity of lower-extremity volume estimates: comparison of calculated volume derived from girth measurements and water displacement volume.
As previously reported, the LEL index allows body type corrected lymphoedematous volume evaluation, as it is adjusted by taking body physique or BMI into consideration.
Practicality of lower extremity lymphedema index: lymphedema index versus volumetry-based evaluations for body-type corrected lower extremity volume evaluation.
Definition of LED with LEL index of 250 or higher is based on results from previous studies that most limbs of progressed lymphoedema patients with significant lymphoedematous volume change had a LEL index of 250 or higher, and that no healthy volunteer limb showed a LEL index over 250.
Practicality of lower extremity lymphedema index: lymphedema index versus volumetry-based evaluations for body-type corrected lower extremity volume evaluation.
The earliest finding of indocyanine green lymphography in asymptomatic limbs of lower extremity lymphedema patients secondary to cancer treatment: the modified dermal backflow stage and concept of subclinical lymphedema.
Overview of treatment options and review of the current role and use of compression garments, intermittent pumps, and exercise in the management of lymphedema.
Characteristic indocyanine green lymphography findings in lower extremity lymphedema: the generation of a novel lymphedema severity staging system using dermal backflow patterns.
The earliest finding of indocyanine green lymphography in asymptomatic limbs of lower extremity lymphedema patients secondary to cancer treatment: the modified dermal backflow stage and concept of subclinical lymphedema.
After pelvic cancer treatments, lymph flows are obstructed in the pelvic region with the risk of lymphoedema development. Even before subjective symptom manifestations, abnormal lymph circulation can be reflected in dermal backflow, which is defined as subclinical lymphoedema; on ICG lymphography, this reversible lymph backflow is seen as a splash pattern.
Characteristic indocyanine green lymphography findings in lower extremity lymphedema: the generation of a novel lymphedema severity staging system using dermal backflow patterns.
The earliest finding of indocyanine green lymphography in asymptomatic limbs of lower extremity lymphedema patients secondary to cancer treatment: the modified dermal backflow stage and concept of subclinical lymphedema.
When lymphatic collateral pathways fail to compensate for lymph overload, irreversible lymph backflow occurs, and leads to symptomatic progressive lymphoedema; this irreversible lymph backflow is seen as a stardust or diffuse pattern on ICG lymphography.
Characteristic indocyanine green lymphography findings in lower extremity lymphedema: the generation of a novel lymphedema severity staging system using dermal backflow patterns.
The earliest finding of indocyanine green lymphography in asymptomatic limbs of lower extremity lymphedema patients secondary to cancer treatment: the modified dermal backflow stage and concept of subclinical lymphedema.
With progression of lymphoedema, the lower extremity becomes dysmorphic, which causes clinically significant problems in cosmesis and function of the affected limb.
Practicality of lower extremity lymphedema index: lymphedema index versus volumetry-based evaluations for body-type corrected lower extremity volume evaluation.
Characteristic indocyanine green lymphography findings in lower extremity lymphedema: the generation of a novel lymphedema severity staging system using dermal backflow patterns.
The earliest finding of indocyanine green lymphography in asymptomatic limbs of lower extremity lymphedema patients secondary to cancer treatment: the modified dermal backflow stage and concept of subclinical lymphedema.
To prevent clinical morbidities in LEL patients, it is important to clarify factors associated with LED. Previous reports revealed that ICG lymphography was useful for early diagnosis of secondary LEL.
Characteristic indocyanine green lymphography findings in lower extremity lymphedema: the generation of a novel lymphedema severity staging system using dermal backflow patterns.
The earliest finding of indocyanine green lymphography in asymptomatic limbs of lower extremity lymphedema patients secondary to cancer treatment: the modified dermal backflow stage and concept of subclinical lymphedema.
However, there has been no study that reports an association between progressed LEL with LED and ICG lymphography findings. This is the first report that has clarified a strong association between LED and ICG lymphography.
As revealed in this study, ICG lymphography based LDB stage has the strongest association with LED which is commonly seen in progressed LEL cases. ICG lymphography plays an important role in the evaluation of both early and late stage lymphoedema.
Characteristic indocyanine green lymphography findings in lower extremity lymphedema: the generation of a novel lymphedema severity staging system using dermal backflow patterns.
The earliest finding of indocyanine green lymphography in asymptomatic limbs of lower extremity lymphedema patients secondary to cancer treatment: the modified dermal backflow stage and concept of subclinical lymphedema.
In the management of lymphoedema, many patients have been seen with discrepancy between clinical severity, severity staging systems based on, for example, the International Society of Lymphology (ISL) stage or Campisi stage, and prognosis or progression of lymphoedema; some patients with ISL stage 2 lymphoedema show aggressive progression refractory to treatments, whereas others are responsive to and controlled by treatments.
Previous studies revealed that ICG lymphography allowed better stratification of lymphoedema progression risk; ISL stage 0 could be classified into three stages, LDB stages 0, I, and II with differing prognoses.
The earliest finding of indocyanine green lymphography in asymptomatic limbs of lower extremity lymphedema patients secondary to cancer treatment: the modified dermal backflow stage and concept of subclinical lymphedema.
As ICG lymphography allows the clearest visualisation of superficial lymph flows, severity staging based on LDB stage would be useful for evaluation of the pathophysiological conditions of lymphoedema.
Characteristic indocyanine green lymphography findings in lower extremity lymphedema: the generation of a novel lymphedema severity staging system using dermal backflow patterns.
The earliest finding of indocyanine green lymphography in asymptomatic limbs of lower extremity lymphedema patients secondary to cancer treatment: the modified dermal backflow stage and concept of subclinical lymphedema.
If a patient shows mild lymphoedema but progressed stage in LDB stage, medical staff should consider more progressive treatment than that suggested by its clinical appearance.
The earliest finding of indocyanine green lymphography in asymptomatic limbs of lower extremity lymphedema patients secondary to cancer treatment: the modified dermal backflow stage and concept of subclinical lymphedema.
Limitations of the study included its design, a retrospective observational study. Further clinical studies are required to confirm that the LED associated factors revealed in this study are useful to predict the disease progression with poor quality of life, and that progressive interventions to high risk patients prevent progression of LEL. This study included only female LEL patients secondary to pelvic cancer treatments. Therefore, it is still unclear whether the results are applicable to primary LEL, male LEL, and LEL secondary to inguinal lymph node dissection. Other factors such as operative procedures of pelvic cancer surgery and extension or type of lymph node dissection could be associated with LED, but could not be included in this study because relevant records were not available.
Recently, various effective and less invasive surgical treatments have been reported to be useful for the management of progressive LEL refractory to conservative treatments.
Navigation lymphatic supermicrosurgery for iatrogenic lymphorrhea: supermicrosurgical lymphaticolymphatic anastomosis and lymphaticovenular anastomosis under indocyanine green lymphography navigation.
LDB stage would be useful when considering indications for surgical treatments for refractory LEL, although further investigations are warranted.
Conclusions
Independent factors associated with LED have been clarified. ICG lymphography based LDB stage had the strongest association with LED. Lymphoedema evaluation using ICG lymphography is useful for progressed LEL with LED. Patients with higher LDB stage should be carefully followed and considered for aggressive treatments.
Acknowledgments
We would like to thank Rico and all members in our department for their kind support of data collection and manuscript preparation.
Conflict of Interest
None.
Funding
Tokyo Metropolitan Clinical Research Grant for Special Research H280402001 (to T.Y.) covered the cost of manuscript preparation. The sponsor had no role in study design, data collection, data analysis, or interpretation of data.
References
Brennan M.J.
Miller L.T.
Overview of treatment options and review of the current role and use of compression garments, intermittent pumps, and exercise in the management of lymphedema.
Practicality of lower extremity lymphedema index: lymphedema index versus volumetry-based evaluations for body-type corrected lower extremity volume evaluation.
Characteristic indocyanine green lymphography findings in lower extremity lymphedema: the generation of a novel lymphedema severity staging system using dermal backflow patterns.
The earliest finding of indocyanine green lymphography in asymptomatic limbs of lower extremity lymphedema patients secondary to cancer treatment: the modified dermal backflow stage and concept of subclinical lymphedema.
Navigation lymphatic supermicrosurgery for iatrogenic lymphorrhea: supermicrosurgical lymphaticolymphatic anastomosis and lymphaticovenular anastomosis under indocyanine green lymphography navigation.
Concurrent validity of lower-extremity volume estimates: comparison of calculated volume derived from girth measurements and water displacement volume.
We read the article by Yamamoto et al. with great interest.1 The authors aimed to examine independent factors associated with lower extremity dysmorphia (LED) in patients with secondary lower extremity lymphoedema. They found that the odds of LED were considerably higher among patients with stage IV leg dermal backflow (LDB) compared with those with stage 0 LDB (crude odds ratio [OR] 43.00, 95% confidence interval [CI] 4.92–375.76; adjusted OR 76.79, 95% CI 8.13–725.20), which is questionable. The authors believe that the very large effect size estimate, such as OR with considerably wide CI, can be yielded from sparse data.
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