- Email: [email protected]
Indocyanine green lymphography for evaluation of genital lymphedema in secondary lower extremity lymphedema patients
Indocyanine green lymphography for evaluation of genital lymphedema in secondary lower extremity lymphedema patients Takumi Yamamoto, MD, Nana Yamamoto, MD, Hidehiko Yoshimatsu, MD, Shinya Hayami, MD, Mitsunaga Narushima, MD, and Isao Koshima, MD Tokyo, Japan Objective: Treatment of genital lymphedema (GL) is challenging, and early diagnosis and intervention is important to prevent progression of GL. However, early treatment of GL is difficult due to a lack of appropriate evaluation methods allowing early diagnosis. We sought to develop a novel pathophysiological evaluation method for early diagnosis of GL using indocyanine green (ICG) lymphography. Methods: This was a retrospective observational study set in a teaching hospital. Patient characteristics and ICG lymphography findings of 68 lower limb lymphedema patients secondary to gynecologic cancer treatments were reviewed. The clinical data and dermal backflow (DB) stages based on ICG lymphography findings were analyzed to compare between the left and right region with and without symptomatic GL.
Results: Twenty-two of 136 lateralities were symptomatic GL. Univariate analyses revealed statistically significant differences between lateralities with (n [ 22) and without GL (n [ 114) in the duration of leg edema (6.3 ± 1.1 vs 3.8 ± 0.5 years; P [ .032), International Society of Lymphology stage (stage 0/1/ 2/3: 0/4/15/3 vs 40/32/32/10; P [ .001), leg DB stage (stage 0/I/II/III/IV/V: 0/0/7/9/4/2 vs 6/35/23/29/ 18/3; P [ .002), and genital DB stage (stage 0/I/II/III/IV: 0/0/0/20/2 vs 27/43/28/16/0; P < .001). Conclusions: ICG lymphography can clearly visualize abnormal lymph circulation in the lower abdominal and genital region. Genital DB stage based on ICG lymphography findings allows early diagnosis of GL before symptom manifestation. Further studies are needed to clarify that ICG lymphography is a key evaluation for prevention and early intervention of GL. (J Vasc Surg: Venous and Lym Dis 2013;1:400-5.)
Treatment of genital lymphedema (GL) is challenging, especially due to difficulty in applying compression to the genital region.1-7 Although female GL is considered to be a less significant clinical problem compared with male GL, which involves distension of the scrotum and the penis, edematous labia in female GL causes urination troubles and genital lymphorrhea, which significantly deteriorates female patients’ quality of life. It is important to diagnose GL at an early stage and to prevent progression of GL by early interventions.8-10 GL usually accompanies lower extremity lymphedema (LEL), several risk factors of which have been reported.11-21 In patients with LEL secondary to pelvic cancer treatments, physicians or therapists who manage the disease should always pay attention to GL. However, no methods have been reported for early diagnosis of GL. Due to lack of evaluation for early diagnosis and pathophysiological severity staging system for
GL, most GL cases deteriorate without therapeutic interventions, and some cases progress to severe condition complicated with lymphorrhea. Recently, we have reported minimally invasive evaluation methods using indocyanine green (ICG) lymphography that clearly visualize abnormal lymph circulation even before manifestation of lymphedema symptoms.22-25 ICG lymphography allows pathophysiological assessment of lymph flows in a small region such as the genital region without radiation exposure, which makes it an ideal modality for evaluation of GL. We reviewed and analyzed clinical data and ICG lymphography findings of secondary LEL patients following pelvic cancer treatments with and without symptomatic GL to clarify significant factors associated with GL.
From the Department of Plastic and Reconstructive Surgery, Graduate School of Medicine, the University of Tokyo. Author conflict of interest: none. Additional material for this article may be found online at www.jvsvenous.org. Reprint requests: Takumi Yamamoto, MD, Department of Plastic and Reconstructive Surgery, Graduate School of Medicine, the University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655 Japan (e-mail: [email protected]). The editors and reviewers of this article have no relevant financial relationships to disclose per the Journal policy that requires reviewers to decline review of any manuscript for which they may have a conflict of interest. 2213-333X/$36.00 Copyright Ó 2013 by the Society for Vascular Surgery. http://dx.doi.org/10.1016/j.jvsv.2013.02.001
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METHODS From April 2009 to December 2010, under the University of Tokyo Hospital ethical committee-approved protocol, we performed ICG lymphography on 68 LEL patients secondary to pelvic cancer treatments who were referred to our department for supermicrosurgical treatment for progressive LEL. Clinical data were retrospectively analyzed according to GL. The etiology of secondary LELs consisted of uterine cervical carcinoma (n ¼ 37), uterine corpus carcinoma (n ¼ 22), and ovarian cancer (n ¼ 9). Patients’ age ranged from 27 to 78 years (average, 52.8 years), duration of leg lymphedema by limb ranged from 0 to 24 years (average, 4.2 years), and LEL index ranged from 184 to 413 (average, 263.5; Appendix [online only]).26 Twenty-seven of 68 patients
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had a past history of radiotherapy, and 35 had a past history of cellulitis. International Society of Lymphology (ISL) stage by limb included stage 0 (n ¼ 40), stage 1 (n ¼ 36), stage 2 (n ¼ 47), and stage 3 (n ¼ 13; Table I).27 All patients gave written consent to this study. ICG lymphography. ICG lymphography was performed as follows: 0.2 mL of ICG (Diagnogreen 0.25%; Daiichi Pharmatical, Tokyo, Japan) was subcutaneously injected in the bilateral lower extremities at the first web space of the foot and the lateral border of the Achilles’ tendon.22,23 After injection, circumferential fluorescent images of lymphatic drainage channels were obtained using an infrared camera system (Photodynamic Eye; Hamamatsu Photonics K.K., Hamamatsu, Japan). ICG lymphography images were recorded 12 to 18 hours after injection and classified into the following dermal backflow patterns: splash, stardust, and diffuse patterns (Fig 1).22-25 The splash pattern consisted of scattered small aggregations of tortuous lines; the stardust pattern demonstrated dimly luminous, spotted fluorescent signals; and, in the diffuse pattern, dye was widely distributed without scattered aggregations or identifiable spots. Based on ICG lymphography findings, leg dermal backflow (LDB) stage was determined by limb as previously reported (Table II; Fig 2).23 In LDB stage I, a splash pattern can be observed around the groin region without other dermal backflow patterns. A stardust pattern appears in LDB stage II-V. In LDB stage II, the stardust pattern is distally limited to the superior border of the patella, whereas in LDB stages III and IV, the stardust pattern exceeds the superior border of the patella. Different from LDB stage III, LDB stages IV
Table I. Patient characteristics (136 genitalia and limbs of 68 patients) Characteristics Age, years Range Average Cause of LEL Uterine cervical carcinoma Uterine corpus carcinoma Ovarian cancer Past history Radiotherapy Cellulitis Duration of LELa (year) Range Average LEL indexa Range Average ISL stagea Stage 0 Stage 1 Stage 2 Stage 3
Counts (%) 27-78 52.8 37 (54.4) 22 (32.4) 9 (13.2) 27 (39.7) 35 (51.5)
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Fig 1. Three types of dermal backflow patterns. The splash pattern (green) consists of scattered small aggregations of tortuous lines, which are observed in subclinical stage of lymphedema (left). With progression of lymphedema, the dermal backflow image changes to a stardust pattern (yellow), which demonstrates dimly luminous, spotted fluorescent signals (center). In the most severe stage of lymphedema, a diffuse pattern (red), which shows widely distributed dye without twinkling or identifiable spots, becomes evident (right).
refers to a condition in which the stardust pattern is present in whole area of the lower extremity. A diffuse pattern becomes evident with presence of the stardust pattern in LDB stage V. Genital dermal backflow (GDB) stage was determined by laterality based on corresponding ICG lymphography findings (Table III); In GDB stage 0, no dermal backflow pattern is observed around the groin, the lower abdomen, or the genital region. In GDB stage I, a splash pattern can be observed around the groin and/or the lower abdominal region without other dermal backflow patterns. In GDB stage II, a stardust pattern is observed around the groin and/or lower abdominal region, but not in the genital region. Different from GDB stage II, GDB stage III refers to a condition in which the stardust pattern is present in whole area between the groin and the genital regions. In GDB stage IV, a diffuse pattern becomes evident with presence of the stardust pattern in the background. Data analysis. Just as the lower extremities consist of two limbs, we separated the area between the lower abdomen and the genitalia in two parts: the left and right regions. Symptomatic GL was diagnosed by those regions
0-24 4.2
Table II. LDB stage based on DB patterns of ICG lymphography
184-413 263.5
Stage 0 Stage I Stage II
40 36 47 13
(29.4) (26.5) (34.6) (9.6)
ISL, International Society of Lymphology; LEL, lower extremity lymphedema. a Data are of the limbs.
Stage III Stage IV Stage V
No dermal backflow pattern Splash pattern around the groin region Stardust pattern extended proximal to the superior border of the patella Stardust pattern extended distal to the superior border of the patella Stardust pattern extended to the whole limb Presence of diffuse pattern with stardust pattern in the background
DB, Dermal backflow; ICG, indocyanine green; LDB, leg dermal backflow.
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Fig 2. Genital dermal backflow (GDB) stage based on indocyanine green (ICG) lymphography findings. In GDB stage 0, no dermal backflow pattern is observed around the groin, the lower abdomen, or the genital region (A). In GDB stage I, a splash pattern (green) can be observed around the groin and/or the lower abdominal region without other dermal backflow patterns (B). In GDB stage II, a stardust pattern (yellow) is observed around the groin and/or lower abdominal region, but not in the genital region (C). Different from GDB stage II, GDB stage III refers to a condition in which the stardust pattern is present in whole area between the groin and the genital regions (D). In GDB stage IV, a diffuse pattern (red) becomes evident with the presence of the stardust pattern in the background (E).
when a patient complained of swelling of the genital region, urination troubles due to the swelling, or genital lymphorrhea. In this study, the lower abdominal region is defined as a region between the level of the umbilicus to the pubic tubercle, and the genital region is defined as a region below the level of the pubic tubercle. Clinical data and dermal backflow stages were compared between the left and right regions with and without symptomatic GL. Mann Whitney U test and c2 test were appropriately used for statistical analyses. Data analysis was done with JMP9 (SAS Institute Japan, Tokyo, Japan). A statistically significant difference was defined as P < .05.
RESULTS Of 136 regions from 68 LEL patients, 22 regions were diagnosed as symptomatic GL. ICG lymphography was successfully performed on all patients without adverse events, need for additional injection of ICG, or artifact influencing severity staging based on ICG lymphography findings. ICG lymphography revealed that 6 limbs were in LDB stage 0, 35 in LDB stage I, 30 in LDB stage II, 38 in LDB stage III, 22 in LDB stage IV, and 5 in LDB stage V. On ICG lymphography, 27 regions were determined to be in GDB stage 0, 43 in GDB stage I,
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Table III. GDB stage based on DB patterns of ICG lymphography Stage 0 Stage I Stage II Stage III Stage IV
No dermal backflow pattern Splash pattern around the groin and/or the lower abdominal region Stardust pattern around the groin and/or the lower abdominal region Stardust pattern extended to the genital region Presence of diffuse pattern with stardust pattern in the background
DB, Dermal backflow; GDB, genital dermal backflow; ICG, indocyanine green.
28 in GDB stage II, 36 in GDB stage III, and 2 in GDB stage IV. Significant differences were observed between the left and right regions with and without symptomatic GL in duration of LEL (6.3 6 1.1 vs 3.8 6 0.5 years; P ¼ .032), ISL stage (stage 0/1/2/3: 0/4/15/3 vs 40/32/ 32/10; P ¼ .001), LDB stage (stage 0/I/II/III/IV/V: 0/0/7/9/4/2 vs 6/35/23/29/18/3; P ¼ .002), and GDB stage (stage 0/I/II/III/IV: 0/0/0/20/2 vs 27/ 43/28/16/0; P < .001) as shown in Table IV. Symptomatic GL was observed in 0/40 (0%) in ISL stage 0, 4/36 (11.1%) in ISL stage 1, 15/47 (31.9%) in ISL stage 2, and 3/13 (23.1%) in ISL stage 3. Symptomatic GL was observed in 0/6 (0%) in LDB stage 0, 0/35 (0%) in LDB stage I, 7/30 (23.3%) in LDB stage II, 9/38 (23.7%) in LDB stage III, 4/22 (18.2%) in LDB stage IV, and 2/5 (40.0%) in LDB stage V. Symptomatic GL was observed in 0/27 (0%) in GDB stage 0, 0/43 (0%) in GDB stage I, 0/28 (0%) in GDB stage II, 20/36 (55.6%) in GDB stage III, and 2/2 (100%) in GDB stage IV. There was no statistically significant difference between the regions with and without past history of radiotherapy in GDB stage (stage 0/I/II/III/IV: 7/20/8/17/2 vs 20/ 23/20/19/0; P ¼ .081). DISCUSSION Management of GL is difficult due to the lack of established treatments, and evaluation of the GL onset risk is also challenging.1-8 Conservative therapies, which are mainstay treatments for extremity lymphedema, often have minimal effect on GL; the complex structure of the genitalia makes it difficult to be compressed. Lymphaticovenular anastomosis (LVA) is becoming a treatment option for compression-refractory extremity lymphedema, and we have reported cases in which patients with long-standing primary GL complicated with severe lymphorrhea were successfully treated with LVA.10,28-38 Although our report showed good results even in long-standing severe cases, it is recommended to perform LVA at an early stage of GL to maximize the treatment efficacy, or to commence manual lymph drainage at an early stage of GL to avoid surgical treatments.1,3,9,10,32 Therefore, it is important to recognize pathophysiology of GL and diagnose GL at an early stage for successful management of GL.
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Table IV. Comparisons between regions with and without symptomatic GL
Variablea Age, years Cause of LEL Uterine cervical carcinoma Uterine corpus carcinoma Ovarian cancer Past history Radiotherapy Cellulitis Duration of LEL LEL index ISL stage Stage 0 Stage 1 Stage 2 Stage 3 LDB stage Stage 0 Stage I Stage II Stage III Stage IV Stage V GDB stage Stage 0 Stage I Stage II Stage III Stage IV
Region with symptomatic GL (n ¼ 22)
Region without symptomatic GL (n ¼ 114)
55.9 6 2.5
52.2 6 1.1
14 (63.6)
60 (52.6)
6 (27.3)
38 (33.3)
2 (9.1)
16 (14.0)
9 (40.9) 14 (63.6) 6.3 6 1.1 282.4 6 10.7
45 (39.5) 56 (49.1) 3.8 6 0.5 259.8 6 4.7
0 4 15 3
(0) (18.2) (68.2) (13.6)
40 32 32 10
(35.1) (28.1) (28.1) (8.7)
0 0 7 9 4 2
(0) (0) (31.8) (40.9) (18.2) (9.1)
6 35 23 29 18 3
(5.3) (30.7) (20.2) (25.4) (15.8) (2.6)
0 0 0 20 2
(0) (0) (0) (90.9) (9.1)
27 43 28 16 0
(23.7) (37.7) (24.6) (14.0) (0)
P .179 .610
.899 .249 .032 .056 .001
.002
<.001
GDB, Genital dermal backflow; GL, genital lymphedema; ISL, International Society of Lymphology; LDB, leg dermal backflow; LEL, lower extremity lymphedema. P values below .05 are listed in bold. a Data presented as number (%) or mean standard error.
Most GL cases accompany LEL secondary to pelvic cancer treatments. After pelvic cancer treatments such as pelvic lymphadenectomy and radiotherapy, lymph flows are obstructed in the pelvic region, leading to both LEL and GL; retrograde lymph flows occur from the pelvic region to the groin region, resulting in further backflows both to the distal region of the leg and to the genital region.1,4,6-11 As shown in the results of this study, patients with progressed LEL are likely to suffer from symptomatic GL. Higher GDB stage, the DB patterns in the genital region, is also a significant factor associated with symptomatic GL. All patients included in this study underwent standardized pelvic lymphadenectomy, which is one of the most common causes of secondary LEL and GL after gynecologic cancer treatments.11,13,15-20 This study revealed that ICG lymphography clearly visualized abnormal lymph circulation in the genital region; ICG lymphography is considered a useful method for diagnosis and severity evaluation of GL in patients with secondary LEL. Twenty-seven (39.7%) patients received postoperative radiation therapy,
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which is another major factor associated with secondary lymphedema.15-20 We postulated that past history of radiotherapy injures the lymphatics in the irradiated region and thus alters the type of ICG lymphography findings. Although this study indicated a tendency that GDB stages of the irradiated regions were higher than those of nonirradiated regions, it was not statistically significant. As we have reported previously, ICG lymphography pattern changes from normal linear pattern to abnormal DB patterns in obstructive peripheral lymphedema; with progression of lymphedema, DB patterns change from a splash pattern, to a stardust pattern, and finally to a diffuse pattern.22-25 Obstruction of lymph flows causes lymphatic hypertension, dilatation, valve insufficiency, and sclerosis of lymphatic vessels distal to the obstruction site, which results in lymph backflow.22-25,39,40 Lymph backflow is visualized as DB patterns on ICG lymphography. Lymph backflow dilates superficial lymphatics such as lymphatic precollectors and capillaries, where splash pattern is observed on ICG lymphography. As lymphedema progresses, extravasation of lymph fluid takes place, represented as spots on ICG lymphography. We defined this as stardust pattern. Finally, as lymph extravasation becomes severe, the number of spots visualized on ICG lymphography increases to the point where spots merge and cannot be distinguished from each other. This condition is defined as a diffuse pattern. ICG lymphography enables visualization of abnormal lymph circulation in the lower abdominal and the genital region of GL patients even before symptom manifestation. In this study, we injected ICG in the foot of LEL patients and could evaluate lymph circulation of the lower abdominal and the genital region. In LEL patients, retrograde lymph backflows occur from the pelvic region through the inguinal lymph nodes to the distal region of the leg and lead to dermal backflow in the groin, the leg, the lower abdominal region, and/or the genital region.1,9,11 Dermal backflow in the groin region connects lymphatics between the thigh region, the groin region, and the lower abdominal region at the layer of the dermis.22,23,39,40 As lymph backflow progresses, dermal backflow extends from the groin, to the lower abdominal region, and to the genital region.23 Therefore, ICG injected in the foot can travel to the lower abdominal and the genital region in LEL patients, and it is not necessary to inject ICG additionally at the genitalia for evaluation of genital lymph circulation in LEL patients. ICG genital lymphography is indicated for all secondary LEL patients in whom ICG leg lymphography is indicated for, and it can be performed as a part of LEL evaluation without additional dye injection or instruments. We have reported that abnormal lymph circulation, observed as DB patterns on ICG lymphography, extends distally from an obstruction site of lymph flow in obstructive extremity lymphedema; DB patterns extend distally from the axilla in arm lymphedema and from the groin in leg lymphedema.22-24,39,40 Because the genital region is distal to the lower abdominal region in terms of lymph circulation point of view, the concept of lower abdomento-genitalia (LAG) sequence is important for management
of GL; abnormal lymph circulation takes place in the lower abdomen and then in the genitalia.1,6,7,9,10 Although the lower abdomen and the genitalia are continuous in terms of anatomy and lymph circulation, it is important to distinguish the genitalia from the lower abdomen. Unlike the lower abdomen, the genitalia is clinically important, because lymphedematous genitalia causes clinical problems such as urination troubles.2,10,22,23 Lower abdominal lymphedema (LAL), defined as abnormal lymph circulation in the lower abdomen regardless of symptom, precedes GL. Swelling of the lower abdomen is difficult for patients to recognize and is usually misunderstood as obese abdomen. Therefore, diagnosis of LAL is difficult based merely on physical examination; it should be made by detection of abnormal lymph circulation represented by DB patterns on ICG lymphography. Based on the concept of LAG sequence, GDB stage can be subdivided into three clinical phaseseno-lymphedema phase, LAL phase, and GL phase. GDB stage 0 is defined as a no-lymphedema phase, stage I-II as an LAL phase, and GDB stage III-IV as a GL phase. LAL always comes before GL, and its diagnosis can play an important role in early diagnosis and prevention of GL. GDB stage, based on abnormal lymph circulation in the lower abdominal and the genital region, is a pathophysiological severity staging system for GL. ICG genital lymphography allows early diagnosis of GL, even at an asymptomatic subclinical stage. The concept of LAG sequence that LAL precedes GL plays a key role in management of GL, and much attention should be paid to LAL in LEL patients. A limitation of this study is that patients included in the present study had only secondary LEL. Further investigations are needed to clarify the usefulness of GDB stage in primary lymphedema cases or isolated GL cases and to verify the effectiveness of early intervention such as manual lymph drainage and LVA at the LAL phase to prevent GL. CONCLUSIONS The present study revealed that severity of LEL and higher GDB stage were significant factors associated with symptomatic GL in LEL patients secondary to pelvic cancer treatments. ICG lymphography allows visualization of abnormal lymph circulation in the lower abdominal and the genital region, which plays an important role in early diagnosis and treatment of GL. AUTHOR CONTRIBUTIONS Conception and design: TY, SH Analysis and interpretation: TY, NY Data collection: TY, NY, HY, SH, MN, IK Writing the article: TY, NY, HY Critical revision of the article: TY, NY, HY, SH, MN, IK Final approval of the article: TY, NY, HY, SH, MN, IK Statistical analysis: TY, NY Obtained funding: TY Overall responsibility: TY
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23. Yamamoto T, Matsuda N, Doi K, Oshima A, Yoshimatsu H, Todokoro T, et al. The earliest finding of indocyanine green (ICG) lymphography in asymptomatic limbs of lower extremity lymphedema patients secondary to cancer treatment: the modified dermal backflow (DB) stage and concept of subclinical lymphedema. Plast Reconstr Surg 2011;128:314e-21e. 24. Yamamoto T, Yamamoto N, Doi K, Oshima A, Yoshimatsu H, Todokoro T, et al. Indocyanine green-enhanced lymphography for upper extremity lymphedema: a novel severity staging system using dermal backflow patterns. Plast Reconstr Surg 2011;128:941-7. 25. Yamamoto T, Iida T, Matsuda N, Kikuchi K, Yoshimatsu H, Mihara M, et al. Indocyanine green (ICG)-enhanced lymphography for evaluation of facial lymphedema. J Plast Reconstr Aesthet Surg 2011;64:1541-4. 26. Yamamoto T, Matsuda N, Todokoro T, Yoshimatsu H, Narushima M, Mihara M, et al. Lower extremity lymphedema (LEL) index: a simple method for severity evaluation of lower extremity lymphedema. Ann Plast Surg 2011;67:637-40. 27. International Society of Lymphology. The diagnosis and treatment of peripheral lymphedema. 2009 Concensus Document of the International Society of Lymphology. Lymphology 2009;42:51-60. 28. Yamada Y. Studies on lymphatico-venous anastomoses in lymphedema. Nagoya J Med 1969;32:1-21. 29. O’Brien BM. Microlymphaticovenous surgery for obstructive lymphedema. Aust N Z J Surg 1977;47:284-91. 30. Koshima I, Inagawa K, Urushibara K, Moriguchi T. Supermicrosurgical lymphaticovenular anastomosis for the treatment of lymphedema in the upper extremities. J Reconstr Microsurg 2000;16:437-42. 31. Koshima I, Nanba Y, Tsutsui T, Takahashi Y, Itoh S. Long-term follow-up after lymphaticovenular anastomosis for lymphedema in the leg. J Reconstr Microsurg 2003;19:209-15. 32. Koshima I, Nanba Y, Tsutsui T, Takahashi Y, Itoh S, Fujitsu M. Minimal invasive lymphaticovenular anastomosis under local anesthesia for leg lymphedema: is it effective for stage III and IV? Ann Plast Surg 2004;53:261-6. 33. Narushima M, Mihara M, Yamamoto Y, Iida T, Koshima I, Mundinger GS. The intravascular stenting method for treatment of extremity lymphedema with multiconfiguration lymphaticovenous anastomoses. Plast Reconstr Surg 2010;125:935-43. 34. Chang DW. Lymphaticovenular bypass for lymphedema management in breast cancer patients: a prospective study. Plast Reconstr Surg 2010;126:752-8. 35. Yamamoto T, Narushima M, Kikuchi K, Yoshimatsu H, Todokoro T, Mihara M, et al. Lambda-shaped anastomosis with intravascular stenting method for safe and effective lymphaticovenular anastomosis. Plast Reconstr Surg 2011;127:1987-92. 36. Yamamoto T, Yoshimatsu H, Narushima M, Yamamoto N, Koshima I. Split intravascular stents for side-to-end lymphaticovenular anastomosis. Ann Plast Surg 2013; in press. 37. Suami H, Chang DW. Overview of surgical treatments for breast cancer-related lymphedema. Plast Reconstr Surg 2010;126:1853-63. 38. Yamamoto T, Narushima M, Yoshimatsu H, Seki Y, Yamamoto N, Oka A, et al. Minimally invasive lymphatic supermicrosurgery: indocyanine green lymphography-guided simultaneous multisite lymphaticovenular anastomoses via millimeter skin incisions. Ann Plast Surg 2012 Dec 13; [Epub ahead of print]. 39. Koshima I, Kawada S, Moriguchi T, Kajiwara Y. Ultrastructural observations of lymphatic vessels in lymphedema in human extremities. Plast Reconstr Surg 1996;97:397-405. 40. Mihara M, Hara H, Hayashi Y, Narushima M, Yamamoto T, Todokoro T, et al. Pathological steps of cancer-related lymphedema: histological changes in the collecting lymphatic vessels after lymphadenectomy. PLoS One 2012;7:e41126.
Submitted Dec 12, 2012; accepted Feb 12, 2013.
Additional material for this article may be found online at www.jvsvenous.org.
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APPENDIX (online only) Calculation of lower extremity lymphedema (LEL) index LEL index ¼ C1 2 þ C2 2 þ C3 2 þ C4 2 þ C5 2
BMI
A summation of squares of circumferences C1, C2, C3, C4, and C5 (cm) divided by body mass
index (BMI; kg/m2) is defined as the LEL index. C1 denotes circumference at 10 cm above the superior border of the patella, C2 circumference at the superior border of the patella, C3 circumference at 10 cm below the superior border of the patella, C4 circumference at the lateral malleolus, and C5 circumference at the dorsum of the foot.
Results: Twenty-two of 136 lateralities were symptomatic GL. Univariate analyses revealed statistically significant differences between lateralities with (n [ 22) and without GL (n [ 114) in the duration of leg edema (6.3 ± 1.1 vs 3.8 ± 0.5 years; P [ .032), International Society of Lymphology stage (stage 0/1/ 2/3: 0/4/15/3 vs 40/32/32/10; P [ .001), leg DB stage (stage 0/I/II/III/IV/V: 0/0/7/9/4/2 vs 6/35/23/29/ 18/3; P [ .002), and genital DB stage (stage 0/I/II/III/IV: 0/0/0/20/2 vs 27/43/28/16/0; P < .001). Conclusions: ICG lymphography can clearly visualize abnormal lymph circulation in the lower abdominal and genital region. Genital DB stage based on ICG lymphography findings allows early diagnosis of GL before symptom manifestation. Further studies are needed to clarify that ICG lymphography is a key evaluation for prevention and early intervention of GL. (J Vasc Surg: Venous and Lym Dis 2013;1:400-5.)
Treatment of genital lymphedema (GL) is challenging, especially due to difficulty in applying compression to the genital region.1-7 Although female GL is considered to be a less significant clinical problem compared with male GL, which involves distension of the scrotum and the penis, edematous labia in female GL causes urination troubles and genital lymphorrhea, which significantly deteriorates female patients’ quality of life. It is important to diagnose GL at an early stage and to prevent progression of GL by early interventions.8-10 GL usually accompanies lower extremity lymphedema (LEL), several risk factors of which have been reported.11-21 In patients with LEL secondary to pelvic cancer treatments, physicians or therapists who manage the disease should always pay attention to GL. However, no methods have been reported for early diagnosis of GL. Due to lack of evaluation for early diagnosis and pathophysiological severity staging system for
GL, most GL cases deteriorate without therapeutic interventions, and some cases progress to severe condition complicated with lymphorrhea. Recently, we have reported minimally invasive evaluation methods using indocyanine green (ICG) lymphography that clearly visualize abnormal lymph circulation even before manifestation of lymphedema symptoms.22-25 ICG lymphography allows pathophysiological assessment of lymph flows in a small region such as the genital region without radiation exposure, which makes it an ideal modality for evaluation of GL. We reviewed and analyzed clinical data and ICG lymphography findings of secondary LEL patients following pelvic cancer treatments with and without symptomatic GL to clarify significant factors associated with GL.
From the Department of Plastic and Reconstructive Surgery, Graduate School of Medicine, the University of Tokyo. Author conflict of interest: none. Additional material for this article may be found online at www.jvsvenous.org. Reprint requests: Takumi Yamamoto, MD, Department of Plastic and Reconstructive Surgery, Graduate School of Medicine, the University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655 Japan (e-mail: [email protected]). The editors and reviewers of this article have no relevant financial relationships to disclose per the Journal policy that requires reviewers to decline review of any manuscript for which they may have a conflict of interest. 2213-333X/$36.00 Copyright Ó 2013 by the Society for Vascular Surgery. http://dx.doi.org/10.1016/j.jvsv.2013.02.001
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METHODS From April 2009 to December 2010, under the University of Tokyo Hospital ethical committee-approved protocol, we performed ICG lymphography on 68 LEL patients secondary to pelvic cancer treatments who were referred to our department for supermicrosurgical treatment for progressive LEL. Clinical data were retrospectively analyzed according to GL. The etiology of secondary LELs consisted of uterine cervical carcinoma (n ¼ 37), uterine corpus carcinoma (n ¼ 22), and ovarian cancer (n ¼ 9). Patients’ age ranged from 27 to 78 years (average, 52.8 years), duration of leg lymphedema by limb ranged from 0 to 24 years (average, 4.2 years), and LEL index ranged from 184 to 413 (average, 263.5; Appendix [online only]).26 Twenty-seven of 68 patients
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had a past history of radiotherapy, and 35 had a past history of cellulitis. International Society of Lymphology (ISL) stage by limb included stage 0 (n ¼ 40), stage 1 (n ¼ 36), stage 2 (n ¼ 47), and stage 3 (n ¼ 13; Table I).27 All patients gave written consent to this study. ICG lymphography. ICG lymphography was performed as follows: 0.2 mL of ICG (Diagnogreen 0.25%; Daiichi Pharmatical, Tokyo, Japan) was subcutaneously injected in the bilateral lower extremities at the first web space of the foot and the lateral border of the Achilles’ tendon.22,23 After injection, circumferential fluorescent images of lymphatic drainage channels were obtained using an infrared camera system (Photodynamic Eye; Hamamatsu Photonics K.K., Hamamatsu, Japan). ICG lymphography images were recorded 12 to 18 hours after injection and classified into the following dermal backflow patterns: splash, stardust, and diffuse patterns (Fig 1).22-25 The splash pattern consisted of scattered small aggregations of tortuous lines; the stardust pattern demonstrated dimly luminous, spotted fluorescent signals; and, in the diffuse pattern, dye was widely distributed without scattered aggregations or identifiable spots. Based on ICG lymphography findings, leg dermal backflow (LDB) stage was determined by limb as previously reported (Table II; Fig 2).23 In LDB stage I, a splash pattern can be observed around the groin region without other dermal backflow patterns. A stardust pattern appears in LDB stage II-V. In LDB stage II, the stardust pattern is distally limited to the superior border of the patella, whereas in LDB stages III and IV, the stardust pattern exceeds the superior border of the patella. Different from LDB stage III, LDB stages IV
Table I. Patient characteristics (136 genitalia and limbs of 68 patients) Characteristics Age, years Range Average Cause of LEL Uterine cervical carcinoma Uterine corpus carcinoma Ovarian cancer Past history Radiotherapy Cellulitis Duration of LELa (year) Range Average LEL indexa Range Average ISL stagea Stage 0 Stage 1 Stage 2 Stage 3
Counts (%) 27-78 52.8 37 (54.4) 22 (32.4) 9 (13.2) 27 (39.7) 35 (51.5)
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Fig 1. Three types of dermal backflow patterns. The splash pattern (green) consists of scattered small aggregations of tortuous lines, which are observed in subclinical stage of lymphedema (left). With progression of lymphedema, the dermal backflow image changes to a stardust pattern (yellow), which demonstrates dimly luminous, spotted fluorescent signals (center). In the most severe stage of lymphedema, a diffuse pattern (red), which shows widely distributed dye without twinkling or identifiable spots, becomes evident (right).
refers to a condition in which the stardust pattern is present in whole area of the lower extremity. A diffuse pattern becomes evident with presence of the stardust pattern in LDB stage V. Genital dermal backflow (GDB) stage was determined by laterality based on corresponding ICG lymphography findings (Table III); In GDB stage 0, no dermal backflow pattern is observed around the groin, the lower abdomen, or the genital region. In GDB stage I, a splash pattern can be observed around the groin and/or the lower abdominal region without other dermal backflow patterns. In GDB stage II, a stardust pattern is observed around the groin and/or lower abdominal region, but not in the genital region. Different from GDB stage II, GDB stage III refers to a condition in which the stardust pattern is present in whole area between the groin and the genital regions. In GDB stage IV, a diffuse pattern becomes evident with presence of the stardust pattern in the background. Data analysis. Just as the lower extremities consist of two limbs, we separated the area between the lower abdomen and the genitalia in two parts: the left and right regions. Symptomatic GL was diagnosed by those regions
0-24 4.2
Table II. LDB stage based on DB patterns of ICG lymphography
184-413 263.5
Stage 0 Stage I Stage II
40 36 47 13
(29.4) (26.5) (34.6) (9.6)
ISL, International Society of Lymphology; LEL, lower extremity lymphedema. a Data are of the limbs.
Stage III Stage IV Stage V
No dermal backflow pattern Splash pattern around the groin region Stardust pattern extended proximal to the superior border of the patella Stardust pattern extended distal to the superior border of the patella Stardust pattern extended to the whole limb Presence of diffuse pattern with stardust pattern in the background
DB, Dermal backflow; ICG, indocyanine green; LDB, leg dermal backflow.
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Fig 2. Genital dermal backflow (GDB) stage based on indocyanine green (ICG) lymphography findings. In GDB stage 0, no dermal backflow pattern is observed around the groin, the lower abdomen, or the genital region (A). In GDB stage I, a splash pattern (green) can be observed around the groin and/or the lower abdominal region without other dermal backflow patterns (B). In GDB stage II, a stardust pattern (yellow) is observed around the groin and/or lower abdominal region, but not in the genital region (C). Different from GDB stage II, GDB stage III refers to a condition in which the stardust pattern is present in whole area between the groin and the genital regions (D). In GDB stage IV, a diffuse pattern (red) becomes evident with the presence of the stardust pattern in the background (E).
when a patient complained of swelling of the genital region, urination troubles due to the swelling, or genital lymphorrhea. In this study, the lower abdominal region is defined as a region between the level of the umbilicus to the pubic tubercle, and the genital region is defined as a region below the level of the pubic tubercle. Clinical data and dermal backflow stages were compared between the left and right regions with and without symptomatic GL. Mann Whitney U test and c2 test were appropriately used for statistical analyses. Data analysis was done with JMP9 (SAS Institute Japan, Tokyo, Japan). A statistically significant difference was defined as P < .05.
RESULTS Of 136 regions from 68 LEL patients, 22 regions were diagnosed as symptomatic GL. ICG lymphography was successfully performed on all patients without adverse events, need for additional injection of ICG, or artifact influencing severity staging based on ICG lymphography findings. ICG lymphography revealed that 6 limbs were in LDB stage 0, 35 in LDB stage I, 30 in LDB stage II, 38 in LDB stage III, 22 in LDB stage IV, and 5 in LDB stage V. On ICG lymphography, 27 regions were determined to be in GDB stage 0, 43 in GDB stage I,
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Table III. GDB stage based on DB patterns of ICG lymphography Stage 0 Stage I Stage II Stage III Stage IV
No dermal backflow pattern Splash pattern around the groin and/or the lower abdominal region Stardust pattern around the groin and/or the lower abdominal region Stardust pattern extended to the genital region Presence of diffuse pattern with stardust pattern in the background
DB, Dermal backflow; GDB, genital dermal backflow; ICG, indocyanine green.
28 in GDB stage II, 36 in GDB stage III, and 2 in GDB stage IV. Significant differences were observed between the left and right regions with and without symptomatic GL in duration of LEL (6.3 6 1.1 vs 3.8 6 0.5 years; P ¼ .032), ISL stage (stage 0/1/2/3: 0/4/15/3 vs 40/32/ 32/10; P ¼ .001), LDB stage (stage 0/I/II/III/IV/V: 0/0/7/9/4/2 vs 6/35/23/29/18/3; P ¼ .002), and GDB stage (stage 0/I/II/III/IV: 0/0/0/20/2 vs 27/ 43/28/16/0; P < .001) as shown in Table IV. Symptomatic GL was observed in 0/40 (0%) in ISL stage 0, 4/36 (11.1%) in ISL stage 1, 15/47 (31.9%) in ISL stage 2, and 3/13 (23.1%) in ISL stage 3. Symptomatic GL was observed in 0/6 (0%) in LDB stage 0, 0/35 (0%) in LDB stage I, 7/30 (23.3%) in LDB stage II, 9/38 (23.7%) in LDB stage III, 4/22 (18.2%) in LDB stage IV, and 2/5 (40.0%) in LDB stage V. Symptomatic GL was observed in 0/27 (0%) in GDB stage 0, 0/43 (0%) in GDB stage I, 0/28 (0%) in GDB stage II, 20/36 (55.6%) in GDB stage III, and 2/2 (100%) in GDB stage IV. There was no statistically significant difference between the regions with and without past history of radiotherapy in GDB stage (stage 0/I/II/III/IV: 7/20/8/17/2 vs 20/ 23/20/19/0; P ¼ .081). DISCUSSION Management of GL is difficult due to the lack of established treatments, and evaluation of the GL onset risk is also challenging.1-8 Conservative therapies, which are mainstay treatments for extremity lymphedema, often have minimal effect on GL; the complex structure of the genitalia makes it difficult to be compressed. Lymphaticovenular anastomosis (LVA) is becoming a treatment option for compression-refractory extremity lymphedema, and we have reported cases in which patients with long-standing primary GL complicated with severe lymphorrhea were successfully treated with LVA.10,28-38 Although our report showed good results even in long-standing severe cases, it is recommended to perform LVA at an early stage of GL to maximize the treatment efficacy, or to commence manual lymph drainage at an early stage of GL to avoid surgical treatments.1,3,9,10,32 Therefore, it is important to recognize pathophysiology of GL and diagnose GL at an early stage for successful management of GL.
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Table IV. Comparisons between regions with and without symptomatic GL
Variablea Age, years Cause of LEL Uterine cervical carcinoma Uterine corpus carcinoma Ovarian cancer Past history Radiotherapy Cellulitis Duration of LEL LEL index ISL stage Stage 0 Stage 1 Stage 2 Stage 3 LDB stage Stage 0 Stage I Stage II Stage III Stage IV Stage V GDB stage Stage 0 Stage I Stage II Stage III Stage IV
Region with symptomatic GL (n ¼ 22)
Region without symptomatic GL (n ¼ 114)
55.9 6 2.5
52.2 6 1.1
14 (63.6)
60 (52.6)
6 (27.3)
38 (33.3)
2 (9.1)
16 (14.0)
9 (40.9) 14 (63.6) 6.3 6 1.1 282.4 6 10.7
45 (39.5) 56 (49.1) 3.8 6 0.5 259.8 6 4.7
0 4 15 3
(0) (18.2) (68.2) (13.6)
40 32 32 10
(35.1) (28.1) (28.1) (8.7)
0 0 7 9 4 2
(0) (0) (31.8) (40.9) (18.2) (9.1)
6 35 23 29 18 3
(5.3) (30.7) (20.2) (25.4) (15.8) (2.6)
0 0 0 20 2
(0) (0) (0) (90.9) (9.1)
27 43 28 16 0
(23.7) (37.7) (24.6) (14.0) (0)
P .179 .610
.899 .249 .032 .056 .001
.002
<.001
GDB, Genital dermal backflow; GL, genital lymphedema; ISL, International Society of Lymphology; LDB, leg dermal backflow; LEL, lower extremity lymphedema. P values below .05 are listed in bold. a Data presented as number (%) or mean standard error.
Most GL cases accompany LEL secondary to pelvic cancer treatments. After pelvic cancer treatments such as pelvic lymphadenectomy and radiotherapy, lymph flows are obstructed in the pelvic region, leading to both LEL and GL; retrograde lymph flows occur from the pelvic region to the groin region, resulting in further backflows both to the distal region of the leg and to the genital region.1,4,6-11 As shown in the results of this study, patients with progressed LEL are likely to suffer from symptomatic GL. Higher GDB stage, the DB patterns in the genital region, is also a significant factor associated with symptomatic GL. All patients included in this study underwent standardized pelvic lymphadenectomy, which is one of the most common causes of secondary LEL and GL after gynecologic cancer treatments.11,13,15-20 This study revealed that ICG lymphography clearly visualized abnormal lymph circulation in the genital region; ICG lymphography is considered a useful method for diagnosis and severity evaluation of GL in patients with secondary LEL. Twenty-seven (39.7%) patients received postoperative radiation therapy,
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which is another major factor associated with secondary lymphedema.15-20 We postulated that past history of radiotherapy injures the lymphatics in the irradiated region and thus alters the type of ICG lymphography findings. Although this study indicated a tendency that GDB stages of the irradiated regions were higher than those of nonirradiated regions, it was not statistically significant. As we have reported previously, ICG lymphography pattern changes from normal linear pattern to abnormal DB patterns in obstructive peripheral lymphedema; with progression of lymphedema, DB patterns change from a splash pattern, to a stardust pattern, and finally to a diffuse pattern.22-25 Obstruction of lymph flows causes lymphatic hypertension, dilatation, valve insufficiency, and sclerosis of lymphatic vessels distal to the obstruction site, which results in lymph backflow.22-25,39,40 Lymph backflow is visualized as DB patterns on ICG lymphography. Lymph backflow dilates superficial lymphatics such as lymphatic precollectors and capillaries, where splash pattern is observed on ICG lymphography. As lymphedema progresses, extravasation of lymph fluid takes place, represented as spots on ICG lymphography. We defined this as stardust pattern. Finally, as lymph extravasation becomes severe, the number of spots visualized on ICG lymphography increases to the point where spots merge and cannot be distinguished from each other. This condition is defined as a diffuse pattern. ICG lymphography enables visualization of abnormal lymph circulation in the lower abdominal and the genital region of GL patients even before symptom manifestation. In this study, we injected ICG in the foot of LEL patients and could evaluate lymph circulation of the lower abdominal and the genital region. In LEL patients, retrograde lymph backflows occur from the pelvic region through the inguinal lymph nodes to the distal region of the leg and lead to dermal backflow in the groin, the leg, the lower abdominal region, and/or the genital region.1,9,11 Dermal backflow in the groin region connects lymphatics between the thigh region, the groin region, and the lower abdominal region at the layer of the dermis.22,23,39,40 As lymph backflow progresses, dermal backflow extends from the groin, to the lower abdominal region, and to the genital region.23 Therefore, ICG injected in the foot can travel to the lower abdominal and the genital region in LEL patients, and it is not necessary to inject ICG additionally at the genitalia for evaluation of genital lymph circulation in LEL patients. ICG genital lymphography is indicated for all secondary LEL patients in whom ICG leg lymphography is indicated for, and it can be performed as a part of LEL evaluation without additional dye injection or instruments. We have reported that abnormal lymph circulation, observed as DB patterns on ICG lymphography, extends distally from an obstruction site of lymph flow in obstructive extremity lymphedema; DB patterns extend distally from the axilla in arm lymphedema and from the groin in leg lymphedema.22-24,39,40 Because the genital region is distal to the lower abdominal region in terms of lymph circulation point of view, the concept of lower abdomento-genitalia (LAG) sequence is important for management
of GL; abnormal lymph circulation takes place in the lower abdomen and then in the genitalia.1,6,7,9,10 Although the lower abdomen and the genitalia are continuous in terms of anatomy and lymph circulation, it is important to distinguish the genitalia from the lower abdomen. Unlike the lower abdomen, the genitalia is clinically important, because lymphedematous genitalia causes clinical problems such as urination troubles.2,10,22,23 Lower abdominal lymphedema (LAL), defined as abnormal lymph circulation in the lower abdomen regardless of symptom, precedes GL. Swelling of the lower abdomen is difficult for patients to recognize and is usually misunderstood as obese abdomen. Therefore, diagnosis of LAL is difficult based merely on physical examination; it should be made by detection of abnormal lymph circulation represented by DB patterns on ICG lymphography. Based on the concept of LAG sequence, GDB stage can be subdivided into three clinical phaseseno-lymphedema phase, LAL phase, and GL phase. GDB stage 0 is defined as a no-lymphedema phase, stage I-II as an LAL phase, and GDB stage III-IV as a GL phase. LAL always comes before GL, and its diagnosis can play an important role in early diagnosis and prevention of GL. GDB stage, based on abnormal lymph circulation in the lower abdominal and the genital region, is a pathophysiological severity staging system for GL. ICG genital lymphography allows early diagnosis of GL, even at an asymptomatic subclinical stage. The concept of LAG sequence that LAL precedes GL plays a key role in management of GL, and much attention should be paid to LAL in LEL patients. A limitation of this study is that patients included in the present study had only secondary LEL. Further investigations are needed to clarify the usefulness of GDB stage in primary lymphedema cases or isolated GL cases and to verify the effectiveness of early intervention such as manual lymph drainage and LVA at the LAL phase to prevent GL. CONCLUSIONS The present study revealed that severity of LEL and higher GDB stage were significant factors associated with symptomatic GL in LEL patients secondary to pelvic cancer treatments. ICG lymphography allows visualization of abnormal lymph circulation in the lower abdominal and the genital region, which plays an important role in early diagnosis and treatment of GL. AUTHOR CONTRIBUTIONS Conception and design: TY, SH Analysis and interpretation: TY, NY Data collection: TY, NY, HY, SH, MN, IK Writing the article: TY, NY, HY Critical revision of the article: TY, NY, HY, SH, MN, IK Final approval of the article: TY, NY, HY, SH, MN, IK Statistical analysis: TY, NY Obtained funding: TY Overall responsibility: TY
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23. Yamamoto T, Matsuda N, Doi K, Oshima A, Yoshimatsu H, Todokoro T, et al. The earliest finding of indocyanine green (ICG) lymphography in asymptomatic limbs of lower extremity lymphedema patients secondary to cancer treatment: the modified dermal backflow (DB) stage and concept of subclinical lymphedema. Plast Reconstr Surg 2011;128:314e-21e. 24. Yamamoto T, Yamamoto N, Doi K, Oshima A, Yoshimatsu H, Todokoro T, et al. Indocyanine green-enhanced lymphography for upper extremity lymphedema: a novel severity staging system using dermal backflow patterns. Plast Reconstr Surg 2011;128:941-7. 25. Yamamoto T, Iida T, Matsuda N, Kikuchi K, Yoshimatsu H, Mihara M, et al. Indocyanine green (ICG)-enhanced lymphography for evaluation of facial lymphedema. J Plast Reconstr Aesthet Surg 2011;64:1541-4. 26. Yamamoto T, Matsuda N, Todokoro T, Yoshimatsu H, Narushima M, Mihara M, et al. Lower extremity lymphedema (LEL) index: a simple method for severity evaluation of lower extremity lymphedema. Ann Plast Surg 2011;67:637-40. 27. International Society of Lymphology. The diagnosis and treatment of peripheral lymphedema. 2009 Concensus Document of the International Society of Lymphology. Lymphology 2009;42:51-60. 28. Yamada Y. Studies on lymphatico-venous anastomoses in lymphedema. Nagoya J Med 1969;32:1-21. 29. O’Brien BM. Microlymphaticovenous surgery for obstructive lymphedema. Aust N Z J Surg 1977;47:284-91. 30. Koshima I, Inagawa K, Urushibara K, Moriguchi T. Supermicrosurgical lymphaticovenular anastomosis for the treatment of lymphedema in the upper extremities. J Reconstr Microsurg 2000;16:437-42. 31. Koshima I, Nanba Y, Tsutsui T, Takahashi Y, Itoh S. Long-term follow-up after lymphaticovenular anastomosis for lymphedema in the leg. J Reconstr Microsurg 2003;19:209-15. 32. Koshima I, Nanba Y, Tsutsui T, Takahashi Y, Itoh S, Fujitsu M. Minimal invasive lymphaticovenular anastomosis under local anesthesia for leg lymphedema: is it effective for stage III and IV? Ann Plast Surg 2004;53:261-6. 33. Narushima M, Mihara M, Yamamoto Y, Iida T, Koshima I, Mundinger GS. The intravascular stenting method for treatment of extremity lymphedema with multiconfiguration lymphaticovenous anastomoses. Plast Reconstr Surg 2010;125:935-43. 34. Chang DW. Lymphaticovenular bypass for lymphedema management in breast cancer patients: a prospective study. Plast Reconstr Surg 2010;126:752-8. 35. Yamamoto T, Narushima M, Kikuchi K, Yoshimatsu H, Todokoro T, Mihara M, et al. Lambda-shaped anastomosis with intravascular stenting method for safe and effective lymphaticovenular anastomosis. Plast Reconstr Surg 2011;127:1987-92. 36. Yamamoto T, Yoshimatsu H, Narushima M, Yamamoto N, Koshima I. Split intravascular stents for side-to-end lymphaticovenular anastomosis. Ann Plast Surg 2013; in press. 37. Suami H, Chang DW. Overview of surgical treatments for breast cancer-related lymphedema. Plast Reconstr Surg 2010;126:1853-63. 38. Yamamoto T, Narushima M, Yoshimatsu H, Seki Y, Yamamoto N, Oka A, et al. Minimally invasive lymphatic supermicrosurgery: indocyanine green lymphography-guided simultaneous multisite lymphaticovenular anastomoses via millimeter skin incisions. Ann Plast Surg 2012 Dec 13; [Epub ahead of print]. 39. Koshima I, Kawada S, Moriguchi T, Kajiwara Y. Ultrastructural observations of lymphatic vessels in lymphedema in human extremities. Plast Reconstr Surg 1996;97:397-405. 40. Mihara M, Hara H, Hayashi Y, Narushima M, Yamamoto T, Todokoro T, et al. Pathological steps of cancer-related lymphedema: histological changes in the collecting lymphatic vessels after lymphadenectomy. PLoS One 2012;7:e41126.
Submitted Dec 12, 2012; accepted Feb 12, 2013.
Additional material for this article may be found online at www.jvsvenous.org.
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APPENDIX (online only) Calculation of lower extremity lymphedema (LEL) index LEL index ¼ C1 2 þ C2 2 þ C3 2 þ C4 2 þ C5 2
BMI
A summation of squares of circumferences C1, C2, C3, C4, and C5 (cm) divided by body mass
index (BMI; kg/m2) is defined as the LEL index. C1 denotes circumference at 10 cm above the superior border of the patella, C2 circumference at the superior border of the patella, C3 circumference at 10 cm below the superior border of the patella, C4 circumference at the lateral malleolus, and C5 circumference at the dorsum of the foot.