- Email: [email protected]
Indocyanine green lymphography is superior to lymphoscintigraphy in imaging diagnosis of secondary lymphedema of the lower limbs
Indocyanine green lymphography is superior to lymphoscintigraphy in imaging diagnosis of secondary lymphedema of the lower limbs Makoto Mihara, MD,a Hisako Hara, MD,a Mitsunaga Narushima, MD,a Takeshi Todokoro, MD,a Takuya Iida, MD,a Hiroshi Ohtsu, MS,b Noriyuki Murai, MD,c and Isao Koshima, MD,a Tokyo and Saitama, Japan Objective: Lymphedema is commonly viewed as difficult to treat, but lymphaticovenous anastomosis applied early after onset can be curative in some cases. Therefore, early diagnosis of cancer-related lymphedema is important. Lymphoscintigraphy is currently the most common method used for imaging diagnosis of lymphedema, but indocyanine green fluorescence lymphangiography (ICG lymphography) is also increasingly used for this purpose. The goal of this study was to compare the accuracy of these methods for diagnosis of lymphedema. Methods: This was a prospective comparative study, conducted at a general hospital in Japan. The subjects were 29 consecutive patients (all female; age range, 32-79 years) with lymphedema (58 limbs, including healthy ones) after gynecologic cancer care who underwent lymphedema treatment at The University of Tokyo and Saiseikai Kawaguchi General Hospital between April 2011 and December 2011. All subjects were referred to our department for lower extremity lymphoscintigraphy and
ICG lymphography. The sensitivity and specificity of lymphoscintigraphy and ICG lymphography were calculated for all limbs and for diagnosis of early lymphedema in affected limbs (International Society of Lymphology stages 0 and I). In each analysis, receiver-operating characteristic curves were prepared to compare the accuracy of the two methods. Results: In receiver-operating characteristic analysis of 58 limbs, the area under the curve was 0.72642 for lymphoscintigraphy and 0.90943 for ICG lymphography. In 34 limbs with early lymphedema, the area under the curve was 0.55882 for lymphoscintigraphy and 0.81471 for ICG lymphography. Conclusions: ICG lymphography was more accurate than lymphoscintigraphy for detecting lymphedema and was particularly useful for diagnosis of early lymphedema. This is clinically important since early diagnosis may permit curative treatment of lymphedema. (J Vasc Surg: Venous and Lym Dis 2013;1:194-201.)
Lymphedema damages patients’ quality of life because of the enlargement and decreased mobility of the affected limb and repeating cellulitis. Early diagnosis is important for effective treatment of cancer-related lymphedema.1-3 Compression with elastic stockings and conservative treatment with manual lymph drainage are often performed for lymphedema, but treatment using microsurgery has shown increasingly favorable outcomes.4-6 Campisi et al obtained good outcomes in surgery for early lymphedema,7,8 and we have shown achieved complete healing using lymphaticovenous anastomosis for early lymphedema.9 The International Society of Lymphology (ISL) classification is currently the most widely accepted diagnostic criteria for lymphedema but is based on subjective and objective
symptoms of edema and does not reflect abnormal lymph circulation, which is problematic.10 Lymphedema slowly progresses over a long period, and patients themselves and physicians may not notice the appearance and progression of volume increasing caused by edema, delaying initiation of treatment. On the other hand, patients may subjectively feel a strange sensation and pain in the limbs despite no apparent edema being observed. Pain is included in symptoms of lymphedema in some reports,11,12 and we do not have to overlook pain so as to detect early-stage lymphedema. Lymphoscintigraphy is currently the most common method for visualizing abnormal lymph circulation.13-15 However, indocyanine green (ICG) fluorescence lymphangiography (henceforth referred to as ICG lymphography) facilitates real-time low-invasive examination without radiation exposure.16,17 Various researchers reported the usefulness of this method for diagnosis of early lymphedema.7,18-21 In normal limbs, a linear pattern can be seen in ICG lymphgraphy. A splash pattern appears in very early lymphedema, proceeding on to a stardust pattern as the lymphedema becomes severe. We can see a diffuse pattern in late-stage lymphedema limbs. However, a comparison of the accuracy of lymphoscintigraphy and ICG lymphography for the diagnosis of lower limb lymphedema has not been performed. In this study, we examined the sensitivity and specificity of these methods in patients with lymphedema after surgery and maybe even radiation for gynecological cancer. Thus, the objective of the study was to compare the utility of lymphoscintigraphy and ICG lymphography for diagnosis of cancer-related secondary lymphedema.
From the Department of Plastic Surgery and Reconstructive Surgery,a and the Department of Clinical Trial Data Management, Graduate School of Medicine,b The University of Tokyo, Tokyo; and the Department of Vascular Surgery, Saiseikai Kawaguchi General Hospital, Saitama.c Supported by a grant from the Japanese funding program for next generation world-leading research (NEXT program; LS039). Author conflict of interest: none. Additional material for this article may be found online at www.jvsvenous.org. Reprint requests: Makoto Mihara, MD, Department of Plastic and Reconstructive Surgery, University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo, Japan, 113-8655 (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.2012.07.011
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Table. Case characteristics and the results Number Case Gender Age 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29
1R 1L 2R 2L 3R 3L 4R 4L 5R 5L 6R 6L 7R 7L 8R 8L 9R 9L 10R 10L 11R 11L 12R 12L 13R 13L 14R 14L 15R 15L 16R 16L 17R 17L 18R 18L 19R 19L 20R 20L 21R 21L 22R 22L 23R 23L 24R 24L 25R 25L 26R 26L 27R 27L 28R 28L 29R 29L
Primary disease
Duration of Medical ISL ICG lymphedema Radiation interview staging Lymphoscintigraphy lymphography
Female
52
Cervical cancer
6
Female
62
Endometiral cancer
80
Female
54
Fallopian tube cancer
50
Female
57
Cervical cancer
70
Female
63
Cervical cancer
120
Female
79
Endometiral cancer
Female
59
Ovarian cancer
200
Female
79
Cervical cancer
8
Female
52
Cervical cancer
20
Female
65
Cervical cancer
200
Female
62
Cervical cancer
70
Female
53
Cervical cancer
80
Female
44
Uterine sarcoma
30
Female
44
Cervical cancer
80
Female
70
Endometiral cancer
Female
62
Cervical cancer
40
þ
Female
54
Cervical cancer
6
þ
Female
40
Cervical cancer
100
þ
Female
59
Cervical cancer
20
Female
63
Endometiral cancer
30
Female
63
Cervical cancer
10
þ
Female
77
Cervical cancer
120
þ
Female
43
Cervical cancer
120
þ
Female
68
Cervical cancer
20
þ
Female
32
Cervical cancer
10
Female
67
Endometiral cancer
50
Female
57
Endometiral cancer
6
Female
57
Endometiral cancer
6
Female
63
Cervical cancer
þ
80
þ
þ
þ
6
80
þ
1 1 1 1 1 1 0 1 1 1 1 1 1 0 1 1 1 1 1 1 1 1 1 1 0 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 0 1 1 1 1 1 1 1 1 1 0 1 1 1 1 1 1
1 0 2b 1 1 3 0 2a 0 2b 1 1 2b 0 2a 1 2b 0 3 2b 2a 0 1 1 0 1 2b 0 1 1 2a 2b 0 1 2b 2a 2a 1 2b 3 2b 0 2b 2b 1 1 2a 0 2b 1 2a 0 0 1 1 1 1 1
1 1 3 1 1 3 1 4 1 3 1 1 1 1 3 1 3 1 4 4 4 1 1 1 1 1 4 1 1 1 3 3 1 1 2 1 1 2 3 3 2 1 3 4 2 2 1 1 2 1 3 1 1 5 1 1 1 1
1 1 3 1 1 5 0 4 0 3 0 1 2 1 5 5 3 1 5 4 5 1 1 1 0 0 3 0 0 0 3 4 1 2 4 3 3 4 5 5 2 0 5 5 3 3 3 1 3 2 3 0 1 4 3 3 3 3
ICG, Indocyanine green; ISL, International Society of Lymphology; L, left; R, right.
METHODS Patients. The subjects were 29 consecutive patients (58 limbs) who attended lymphedema clinic (M.M.) at
The University of Tokyo and Saiseikai Kawaguchi General Hospital between April 2011 and December 2011. Patients whose subjective symptoms persisted for less
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Fig 1. The correlation between indocyanine green (ICG) or lymphography and International Society of Lymphology (ISL) stage. a, In lymphoscintigraphy, 34 out of 58 limbs were classified as grade 0, which represent normal findings. b, In ICG lymphography, only nine limbs were classified as grade 1, which represent normal.
than 6 months were excluded to rule out indefinite complaint. The patients were referred for lower extremity lymphoscintigraphy and ICG lymphography after clinical examination by a single consultant clinician with many years of experience in lymphedema care (M.M.). All the patients were female; their age ranged from 32 to 79 years old (Table). The gynecological cancer was uterine cervical cancer in 19 patients, endometrial cancer in seven, ovarian cancer in one, uterine sarcoma in one, and fallopian tube cancer in one. Of the 58 limbs, the ISL classification was stage 0 in 13, stage I in 21, stage IIa in nine, stage IIb in 13, and stage III in two. The study was approved by our institutional review board, and informed consent was obtained from all patients. Medical interview. All patients were interviewed regarding the presence or absence of subjective symptoms of edema in each lower limb. When no subjective symptom was present, the case was regarded as type 0. When the patient was aware of apparent edema due to subjective symptoms such as a strange sensation and a distended feeling, the case was regarded as type 1. Cases with intra-
day variation in which symptoms repeatedly remitted and exacerbated were also included in the type 1 category. ISL lymphedema staging.10 In the ISL classification, stage 0 refers to a latent or subclinical condition where swelling is not evident despite impaired lymph transport. This stage may exist for months or years before overt edema occurs (stages I-III). Stage I represents an early accumulation of fluid that is relatively high in protein content (eg, in comparison with “venous” edema) and subsides with limb elevation. Pitting may occur. Stage IIa signifies that limb elevation alone rarely reduces tissue swelling and pitting is manifest. In stage IIb, the limb may or may not pit as tissue fibrosis supervenes. Stage III encompasses lymphostatic elephantiasis where pitting is absent and trophic skin changes such as acanthosis, fat deposits, and warty overgrowths develop. Lymphoscintigraphy. A Tc-99m-labeled nanocolloid was injected subcutaneously (w20 MBq in 0.1 mL per limb) into the dorsum of the first web space of the foot using a 1-mL syringe and a 27-gauge needle. Penetration of the needle into a blood vessel was excluded by careful aspiration before injection. Massage, warm compresses, and lower limb elevation were not permitted after injection. Half-body anterior and posterior images from the upper abdomen to the toes were obtained with a large field-ofview gamma camera, immediately and at 15, 30, 60, and 90 minutes after tracer injection. Staging based on lymphoscintigraphy was performed using the classification proposed by Maekawa et al14: no abnormal findings (type 1), a dermal backflow pattern (DB) above the knee (type 2), DB from above to below the knee (type 3), DB only below the knee (type 4), and no enhancement (type 5). ICG lymphography. ICG lymphography was performed within 3 months after lymphoscintigraphy. ICG (0.2 mL, Diagnogreen 0.5%; Daiichi Pharmaceutical, Tokyo, Japan) was injected intracutaneously into the bilateral first interdigits. Imaging was performed using a PDE system (Hamamatsu Photonics, Hamamatsu, Japan). Vivid dynamic images of superficial lymphatic flow were obtained within a few minutes after the injection. In this method, the skin surface is illuminated with near-infrared light, and light emitted by ICG absorbed in lymph vessels is imaged using a charge coupled device camera to detect lymph flow in subcutaneous lymph vessels. For staging of lymphedema based on ICG lymphography, the classification proposed by Yamamoto et al was used18,19: normal lymphatic pattern (stage 0; Video A, available online only); abnormal findings, such as splash and stardust patterns, in the inguinal region only (stage 1); a stardust pattern above the knee, but normal lymph flow below the knee (stage 2); a stardust pattern in the inguinal region over the ankle, but normal lymph flow on the distal side from the ankle (stage 3); a stardust pattern spread to the toes (stage 4); and a diffuse pattern (stage 5; Video B, available online only). Statistical analysis. The sensitivity and specificity of lymphoscintigraphy and ICG lymphography were determined based on the findings of the clinical evaluation. If patients have a complaint of pain or an uncomfortable
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feeling in their limbs, we determined this to be positive, because they are thought to be subclinical lymphedema. Receiver-operating characteristic curves were prepared and the area under the curve (AUC) was compared for the two methods. Statistical analysis was performed using JMP software (SAS Institute, Cary, NC). RESULTS A summary of the 29 cases (58 limbs) examined in the study is shown in the Table. All procedures were completed without problems in all patients. Based on the interview, five and 53 limbs were classified as types 0 and 1, respectively; on lymphoscintigraphy, 34, 6, 11, 6, and 1 limb were classified as types 1, 2, 3, 4, and 5, respectively; and on ICG lymphography, 10, 13, 4, 16, 6, and 9 limbs were staged as 0, 1, 2, 3, 4, and 5, respectively. The correlation between lymphoscintigraphy, ICG lymphography, or ISL staging is shown in Fig 1. In lymphoscintigraphy, 34 out of 58 limbs were classified as grade 0, which represent normal findings (Fig 2, a and d). On the other hand, in ICG lymphography, only nine limbs were classified as grade 1, which represents normal (Fig 2, b and e). This difference may show the advantage of ICG lymphography in diagnosing early-stage lymphedema. The sensitivity and specificity of lymphscintigraphy was 0.45 and 1.00, respectively; of ICG lymphography was
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0.89 and 0.80, respectively. The AUC on receiveroperating characteristic analysis of the 58 limbs was 0.72642 for lymphoscintigraphy (Fig 2, a), 0.90943 for ICG lymphography (Fig 2, b), and 0.9245 for ISL staging (Fig 2, c). In the 34 limbs with early lymphedema (ISL stages 0-1), the AUC was 0.55882 for lymphoscintigraphy (Fig 2, d), 0.81471 for ICG lymphography (Fig 2, e), and 0.8088 for ISL staging (Fig 2, f). To illustrate these results further, we present findings from one normal case (not included in our series) and two representative lymphedema cases. The patient in case 0 was a 61-year-old woman who had a complaint of bilateral lower limb edema. She had no medical history. We performed lymphscintigraphy and ICG lymphography, and no abnormal findings could be seen (Fig 3). The patient in case 1 was a 52-year-old woman who underwent hysterectomy and lymph node dissection for cervical cancer 2 years ago. Discomfort of the medial sides of the bilateral thighs had appeared starting from the right lower limb 6 months ago and slowly aggravated. Conservative treatment with lymph massage was used immediately after the appearance of the subjective symptom, but the symptom was not remitted. A physical examination revealed no enlargement of the circumference of the bilateral lower limbs. Pitting edema was sometimes noted on
Fig 2. Receiver-operating characteristic curve of indocyanine green (ICG) lymphography, lymphoscintigraphy, and International Society of Lymphology (ISL) classification. a, ICG lymphography, (b) lymphoscintigraphy, (c) ISL classification, (d) ICG lymphography, (e) lymphoscintigraphy, and (f) ISL classification in early-stage lymphedema, respecively.
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the anterior surface of the bilateral lower thigh in the afternoon. On lymphoscintigraphy, there was no dermal backflow in the bilateral lower limbs (right limb: type 1, left limb: type 1; Fig 4, a). In ICG lymphography (right limb: stage 1; left limb: stage 1; Fig 4, b-e), several vivid dynamic images of a superficial lymphatic linear pattern, indicating normal lymphatic flow, in the bilateral dorsi of the feet and lower and distal thigh areas were obtained within a few minutes after injection (Fig 4, d and e). A stardust pattern indicating mildly damaged lymph flow was present in the bilateral proximal thighs and lower abdomen area (Fig 4, c). The patient in case 11 was a 62-year-old Japanese woman who had noted worsening edema in her right lower limb for about 6 years. She had previously undergone extended hysterectomy with lymph node dissection for cervical cancer without radiation therapy. Despite constant and strong compressive therapy with an elastic stocking for 5 years, the edema gradually progressed, and cellulitis in her right thigh recurred every 2 to 3 months. A physical examination revealed enlargement of the circumference
of the right lower extremity of 4 cm at the thigh, 3 cm at the knee, 3 cm at the calf, and 2 cm at the ankle compared with the left extremity. On lymphoscintigraphy, dermal backflow was noted in only the right lower thigh (right limb: type 5; left limb: type 1; Fig 5, a). In ICG lymphography, several vivid dynamic images of a superficial lymphatic linear pattern, indicating normal lymphatic flow, in the right lateral knee and left lower limb were obtained within a few minutes after injection (right limb: stage 5; left limb: stage 1; Figs 5, b and c, and 6). A splash pattern indicating pressure elevation in the lymph network was present in the right dorsum of the foot and bilateral groin (Fig 6, b). A stardust pattern indicating mildly damaged lymph flow was present in the right thigh (Fig 6, c), and a diffuse pattern indicating severely damaged lymph flow was observed in the right lower thigh (Fig 6, d). DISCUSSION We compared the accuracy of ICG lymphography and lymphoscintigraphy in patients with secondary lymphedema of the lower limbs and found that the ICG method was
Fig 3. Case 0. a, Lymphoscintigraphy. The lymph vessels were normal in the bilateral legs. b, Physical findings and indocyanine green (ICG) lymphography patterns. Physically, there was no difference in the circumferences of the bilateral legs. In ICG lymphography, a linear pattern (LP) was found in the bilateral lower limbs. c, ICG lymphography of the left lower limb, showing an LP. LN, Lymph node.
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Fig 4. Case 1. a, Lymphoscintigraphy. The lymph vessels were normal in the bilateral legs. b, Physical findings and indocyanine green (ICG) lymphography patterns. Physically, there was no difference in the circumferences of the bilateral legs. In ICG lymphography, a stardust pattern (SD) was found in the proximal medial regions of the bilateral thighs and lower abdominal region. A linear pattern (LP) was observed in the bilateral distal thighs to the toes. c, ICG lymphography of the lower abdominal and pubic area and proximal thigh region, showing a marked SD. d, ICG lymphography showing an LP in the medial crus. e, ICG lymphography showing an LP in the bilateral dorsi of the feet and ankle joints.
Fig 5. Case 11. a, Lymphoscintigraphy. Dermal backflow patterns were noted mainly in the medial region of the right crus. Lymph vessels in the left leg were normal. b, Physical findings and indocyanine green (ICG) lymphography patterns. b and c, In ICG lymphography, a stardust pattern (SD) was found in the bilateral inguinal regions. In the right leg, an SD was observed in the medial thigh and a linear pattern (LP) in the knee. A splash pattern (SP) was present in the dorsum of the right foot. In the left leg, an LP was present distal from the inguinal region. DP, Diffuse pattern.
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Fig 6. Indocyanine green (ICG) lymphography findings in case 11. a, A stardust pattern in the medial region of the right thigh. b, A diffuse pattern in the medial region of the right crus. c, A splash pattern in the dorsum of the right foot and ankle joint. d, A linear pattern in the dorsum of the left foot and ankle joint.
more accurate than lymphoscintigraphy. The sensitivity and specificity of lymphoscintigraphy were both low for early diagnosis of lymphedema (0.11 and 0.00, respectively), whereas those of ICG lymphography were very high (0.76 and 0.80, respectively), showing the particular utility of this method for early diagnosis. Both lymphoscintigraphy and ICG lymphgraphy show lymphatic flow or dermal backflow if there is lymphatic impairment. The advantages of ICG lymphography compared with lymphoscintigraphy are the absence of radiation exposure, the short time required for the test, usefulness for lymphedema clinical stratification, and the real-time visualization of lymph flow. Also, since ICG lymphography can be used during surgery, it is very useful for searching for lymph vessels suitable for lymphaticovenous anastomosis. Furthermore, since images in lymphoscintigraphy can be acquired in the anteroposterior direction only, regions likely to retain lymph in the early stage, such as the medial region of the thigh, anatomically
overlap healthy collecting lymph vessels in these regions, making visualization of mild dermal backflow patterns difficult. In contrast, the camera position can be freely changed in ICG lymphography, enabling acquisition in all directions. Therefore, the whole affected limb can be examined, and this may be the cause of the greater accuracy of ICG lymphography for early diagnosis of lymphedema. However, ICG lymphography has the disadvantage that only regions at a depth up to 2 cm from the skin can be observed, whereas lymphatic function can be observed in all layers using lymphoscintigraphy. Therefore, more detailed evaluation of lymphatic function and identification of the location of lymph vessels are possible using ICG lymphography and lymphoscintigraphy in combination. Abnormalities were detected by ICG lymphography in patients with no subjective symptoms. Burnand et al observed abnormality in the opposite lower limb in a patient with unilateral lower limb lymphedema with no subjective symptoms and diagnosed this condition as lymph vascular dysfunction.20 Yamamoto et al found that abnormal findings may be observed on ICG lymphography in the absence of subjective symptoms of edema and suggested that this indicates a very early finding of lymphedema.18-21 In gynecological cancer treatment, pelvic or para-aortic lymph node dissection is performed, and it is likely that lymph vascular dysfunction will occur on the ipsilateral side, even though lymphedema is currently present only on the unilateral side.22-25 The findings of abnormalities in ICG lymphography in the absence of subjective symptoms in our patients also suggests the presence of early lymphedema. However, the possibility of false-positive findings cannot be ruled out, and periodic course observation is required following abnormal findings on ICG lymphography. We note that the ICG method itself may be appropriate for continuous observation because of the absence of radiation exposure.16-19 We also found that cases in which patients described a strange sensation and pain without apparent edema were lymphedema-positive. It is clear that these symptoms are associated with lymphedema, and avoidance of overlooking such symptoms may contribute to the early diagnosis of lymphedema. Indication of surgical treatment for lymphedema can be decided when the abnormal pattern in ICG lymphgraphy expands or proceeds to the next stage. Since the subjects were limited to patients with secondary lymphedema after surgery for gynecological cancer, we used classifications that reflected the progression of lymphedema severity based on advancement from proximal to distal regions for grading abnormal findings on lymphoscintigraphy and ICG lymphography.14,18,19 However, this approach does not apply to primary lymphedema, in which specific findings are observed in many cases. Therefore, a further investigation is necessary for cases of primary lymphedema. However, within this limitation, we conclude that ICG lymphography is more accurate than lymphoscintigraphy for diagnosis of lymphedema and that the ICG method is particularly useful for diagnosis of early lymphedema.
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Also, the correlation between the results of surgery and the ICG lymphography is another problem. More research is needed. In conclusion, ICG lymphography was more accurate than lymphoscintigraphy for detecting lymphedema and was particularly useful for the diagnosis of early lymphedema. This is clinically important since early diagnosis may permit curative treatment of lymphedema.
11.
12. 13.
The authors are grateful to Dr Akio Hirota (Hirota Internal Medicine Clinic) for his advice. 14.
AUTHOR CONTRIBUTIONS Conception and design: MM, HH, MN, TT, TI Analysis and interpretation: MM, HH, MN, TT, TI, NM, TK Data collection: MM, HH Writing the article: MM, HH Critical revision of the article: MM Final approval of the article: MM Statistical analysis: HO Obtaining funding: MM Overall responsibility: MM MM and HH contributed equally to this work. REFERENCES 1. Raju S, Furrh JB 4th, Neglen P. Diagnosis and treatment of venous lymphedema. J Vasc Surg 2012;55:141-9. 2. Tam EK, Shen L, Munneke JR, Ackerson LM, Partee PN, Somkin CP, et al. Clinician awareness and knowledge of breast cancer-related lymphedema in a large, integrated health care delivery setting. Breast Cancer Res Treat 2012;131:1029-38. 3. Mehrara BJ, Zampell JC, Suami H, Chang DW. Surgical management of lymphedema: past, present, and future. Lymphat Res Biol 2011;9:159-67. 4. Mukenge SM, Catena M, Negrini D, Ratti F, Moriondo A, Briganti A, et al. Assessment and follow-up of patency after lymphovenous microsurgery for treatment of secondary lymphedema in external male genital organs. Eur Urol 2011;60:1114-9. 5. 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. 6. Campisi C, Bellini C, Campisi C, Accogli S, Bonioli E, Boccardo F. Microsurgery for lymphedema: clinical research and long-term results. Microsurgery 2010;30:256-60. 7. Francesco B, Corrado C, Giuseppe M, Emanuela B, Chiara B, Francesco P, et al. Prevention of lymphatic injuries in surgery. Microsurgery 2010;30:261-5. 8. Boccardo FM, Ansaldi F, Bellini C, Accogli S, Taddei G, Murdaca G, et al. Prospective evaluation of a prevention protocol for lymphedema following surgery for breast cancer. Lymphology 2009;42:1-9; Erratum in: Lymphology 2009;42:149. 9. Mihara M, Murai N, Hayashi Y, Hara H, Iida T, Narushima M, et al. Using indocyanine green fluorescent lymphography and lymphaticvenous anastomosis for cancer-related lymphedema. Ann Vasc Surg 2012;26:278.e1-6. 10. Bernas MJ, Witte CL, Witte MH, International Society of Lymphology Executive Committee. The diagnosis and treatment of peripheral
15. 16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
Mihara et al 201
lymphedema: draft revision of the 1995 Consensus Document of the International Society of Lymphology Executive Committee for discussion at the September 3-7, 2001, XVIII International Congress of Lymphology in Genoa, Italy. Lymphology 2001;34:84-91. Hormes JM, Bryan C, Lytle LA, Gross CR, Ahmed RL, Troxel AB, et al. Impact of lymphedema and arm symptoms on quality of life in breast cancer survivors. Lymphology 2010;43:1-13. Lockwood-Rayermann S. Lymphedema in gynecologic cancer survivors: an area for exploration? Cancer Nurs 2007;30:E11-8. de Rezende LF, Pedras FV, Ramos CD, Gurgel MS. Evaluation of lymphatic compensation by lymphoscintigraphy in the postoperative period of breast cancer surgery with axillary dissection. Tumori 2011;97:309-15. Maegawa J, Mikami T, Yamamoto Y, Satake T, Kobayashi S. Types of lymphoscintigraphy and indications for lymphaticovenous anastomosis. Microsurgery 2010;30:437-42. Beveridge N, Allen L, Rogers K. Lymphoscintigraphy in the diagnosis of lymphangiomatosis. Clin Nucl Med 2010;35:579-82. Ogata F, Narushima M, Mihara M, Azuma R, Morimoto Y, Koshima I. Intraoperative lymphography using indocyanine green dye for near-infrared fluorescence labeling in lymphedema. Ann Plast Surg 2007;59:180-4. Ogata F, Azuma R, Kikuchi M, Koshima I, Morimoto Y. Novel lymphography using indocyanine green dye for near-infrared fluorescence labeling. Ann Plast Surg 2007;58:652-5. Yamamoto T, Matsuda N, Doi K, Oshima A, Yoshimatsu H, Todokoro T, et al. 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. Plast Reconstr Surg 2011;128:314e-21e. Yamamoto T, Narushima M, Doi K, Oshima A, Ogata F, Mihara M, et al. Characteristic indocyanine green lymphography findings in lower extremity lymphedema: the generation of a novel lymphedema severity staging system using dermal backflow patterns. Plast Reconstr Surg 2011;127:1979-86. Suami H, Chang DW, Yamada K, Kimata Y. Use of indocyanine green fluorescent lymphography for evaluating dynamic lymphatic status. Plast Reconstr Surg 2011;127:74e-6e. Furukawa H, Osawa M, Saito A, Hayashi T, Funayama E, Oyama A, et al. Microsurgical lymphaticovenous implantation targeting dermal lymphatic backflow using indocyanine green fluorescence lymphography in the treatment of postmastectomy lymphedema. Plast Reconstr Surg 2011;127:1804-11. Burnand KM, Glass DM, Mortimer PS, Peters AM. Lymphatic dysfunction in the apparently clinically normal contralateral limbs of patients with unilateral lower limb swelling. Clin Nucl Med 2012;37: 9-13. Todo Y, Yamamoto R, Minobe S, Suzuki Y, Takeshi U, Nakatani M, et al. Risk factors for postoperative lower-extremity lymphedema in endometrial cancer survivors who had treatment including lymphadenectomy. Gynecol Oncol 2010;119:60-4. Gould N, Kamelle S, Tillmanns T, Scribner D, Gold M, Walker J, et al. Predictors of complications after inguinal lymphadenectomy. Gynecol Oncol 2001;82:329-32. Kridelka FJ, Berg DO, Neuman M, Edwards LS, Robertson G, Grant PT, et al. Adjuvant small field pelvic radiation for patients with high risk, stage IB lymph node negative cervix carcinoma after radical hysterectomy and pelvic lymph node dissection. A pilot study. Cancer 1999;86:2059-65.
Submitted Jan 25, 2012; accepted Jul 15, 2012.
Additional material for this article may be found online at www.jvsvenous.org.
ICG lymphography. The sensitivity and specificity of lymphoscintigraphy and ICG lymphography were calculated for all limbs and for diagnosis of early lymphedema in affected limbs (International Society of Lymphology stages 0 and I). In each analysis, receiver-operating characteristic curves were prepared to compare the accuracy of the two methods. Results: In receiver-operating characteristic analysis of 58 limbs, the area under the curve was 0.72642 for lymphoscintigraphy and 0.90943 for ICG lymphography. In 34 limbs with early lymphedema, the area under the curve was 0.55882 for lymphoscintigraphy and 0.81471 for ICG lymphography. Conclusions: ICG lymphography was more accurate than lymphoscintigraphy for detecting lymphedema and was particularly useful for diagnosis of early lymphedema. This is clinically important since early diagnosis may permit curative treatment of lymphedema. (J Vasc Surg: Venous and Lym Dis 2013;1:194-201.)
Lymphedema damages patients’ quality of life because of the enlargement and decreased mobility of the affected limb and repeating cellulitis. Early diagnosis is important for effective treatment of cancer-related lymphedema.1-3 Compression with elastic stockings and conservative treatment with manual lymph drainage are often performed for lymphedema, but treatment using microsurgery has shown increasingly favorable outcomes.4-6 Campisi et al obtained good outcomes in surgery for early lymphedema,7,8 and we have shown achieved complete healing using lymphaticovenous anastomosis for early lymphedema.9 The International Society of Lymphology (ISL) classification is currently the most widely accepted diagnostic criteria for lymphedema but is based on subjective and objective
symptoms of edema and does not reflect abnormal lymph circulation, which is problematic.10 Lymphedema slowly progresses over a long period, and patients themselves and physicians may not notice the appearance and progression of volume increasing caused by edema, delaying initiation of treatment. On the other hand, patients may subjectively feel a strange sensation and pain in the limbs despite no apparent edema being observed. Pain is included in symptoms of lymphedema in some reports,11,12 and we do not have to overlook pain so as to detect early-stage lymphedema. Lymphoscintigraphy is currently the most common method for visualizing abnormal lymph circulation.13-15 However, indocyanine green (ICG) fluorescence lymphangiography (henceforth referred to as ICG lymphography) facilitates real-time low-invasive examination without radiation exposure.16,17 Various researchers reported the usefulness of this method for diagnosis of early lymphedema.7,18-21 In normal limbs, a linear pattern can be seen in ICG lymphgraphy. A splash pattern appears in very early lymphedema, proceeding on to a stardust pattern as the lymphedema becomes severe. We can see a diffuse pattern in late-stage lymphedema limbs. However, a comparison of the accuracy of lymphoscintigraphy and ICG lymphography for the diagnosis of lower limb lymphedema has not been performed. In this study, we examined the sensitivity and specificity of these methods in patients with lymphedema after surgery and maybe even radiation for gynecological cancer. Thus, the objective of the study was to compare the utility of lymphoscintigraphy and ICG lymphography for diagnosis of cancer-related secondary lymphedema.
From the Department of Plastic Surgery and Reconstructive Surgery,a and the Department of Clinical Trial Data Management, Graduate School of Medicine,b The University of Tokyo, Tokyo; and the Department of Vascular Surgery, Saiseikai Kawaguchi General Hospital, Saitama.c Supported by a grant from the Japanese funding program for next generation world-leading research (NEXT program; LS039). Author conflict of interest: none. Additional material for this article may be found online at www.jvsvenous.org. Reprint requests: Makoto Mihara, MD, Department of Plastic and Reconstructive Surgery, University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo, Japan, 113-8655 (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.2012.07.011
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Table. Case characteristics and the results Number Case Gender Age 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29
1R 1L 2R 2L 3R 3L 4R 4L 5R 5L 6R 6L 7R 7L 8R 8L 9R 9L 10R 10L 11R 11L 12R 12L 13R 13L 14R 14L 15R 15L 16R 16L 17R 17L 18R 18L 19R 19L 20R 20L 21R 21L 22R 22L 23R 23L 24R 24L 25R 25L 26R 26L 27R 27L 28R 28L 29R 29L
Primary disease
Duration of Medical ISL ICG lymphedema Radiation interview staging Lymphoscintigraphy lymphography
Female
52
Cervical cancer
6
Female
62
Endometiral cancer
80
Female
54
Fallopian tube cancer
50
Female
57
Cervical cancer
70
Female
63
Cervical cancer
120
Female
79
Endometiral cancer
Female
59
Ovarian cancer
200
Female
79
Cervical cancer
8
Female
52
Cervical cancer
20
Female
65
Cervical cancer
200
Female
62
Cervical cancer
70
Female
53
Cervical cancer
80
Female
44
Uterine sarcoma
30
Female
44
Cervical cancer
80
Female
70
Endometiral cancer
Female
62
Cervical cancer
40
þ
Female
54
Cervical cancer
6
þ
Female
40
Cervical cancer
100
þ
Female
59
Cervical cancer
20
Female
63
Endometiral cancer
30
Female
63
Cervical cancer
10
þ
Female
77
Cervical cancer
120
þ
Female
43
Cervical cancer
120
þ
Female
68
Cervical cancer
20
þ
Female
32
Cervical cancer
10
Female
67
Endometiral cancer
50
Female
57
Endometiral cancer
6
Female
57
Endometiral cancer
6
Female
63
Cervical cancer
þ
80
þ
þ
þ
6
80
þ
1 1 1 1 1 1 0 1 1 1 1 1 1 0 1 1 1 1 1 1 1 1 1 1 0 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 0 1 1 1 1 1 1 1 1 1 0 1 1 1 1 1 1
1 0 2b 1 1 3 0 2a 0 2b 1 1 2b 0 2a 1 2b 0 3 2b 2a 0 1 1 0 1 2b 0 1 1 2a 2b 0 1 2b 2a 2a 1 2b 3 2b 0 2b 2b 1 1 2a 0 2b 1 2a 0 0 1 1 1 1 1
1 1 3 1 1 3 1 4 1 3 1 1 1 1 3 1 3 1 4 4 4 1 1 1 1 1 4 1 1 1 3 3 1 1 2 1 1 2 3 3 2 1 3 4 2 2 1 1 2 1 3 1 1 5 1 1 1 1
1 1 3 1 1 5 0 4 0 3 0 1 2 1 5 5 3 1 5 4 5 1 1 1 0 0 3 0 0 0 3 4 1 2 4 3 3 4 5 5 2 0 5 5 3 3 3 1 3 2 3 0 1 4 3 3 3 3
ICG, Indocyanine green; ISL, International Society of Lymphology; L, left; R, right.
METHODS Patients. The subjects were 29 consecutive patients (58 limbs) who attended lymphedema clinic (M.M.) at
The University of Tokyo and Saiseikai Kawaguchi General Hospital between April 2011 and December 2011. Patients whose subjective symptoms persisted for less
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Fig 1. The correlation between indocyanine green (ICG) or lymphography and International Society of Lymphology (ISL) stage. a, In lymphoscintigraphy, 34 out of 58 limbs were classified as grade 0, which represent normal findings. b, In ICG lymphography, only nine limbs were classified as grade 1, which represent normal.
than 6 months were excluded to rule out indefinite complaint. The patients were referred for lower extremity lymphoscintigraphy and ICG lymphography after clinical examination by a single consultant clinician with many years of experience in lymphedema care (M.M.). All the patients were female; their age ranged from 32 to 79 years old (Table). The gynecological cancer was uterine cervical cancer in 19 patients, endometrial cancer in seven, ovarian cancer in one, uterine sarcoma in one, and fallopian tube cancer in one. Of the 58 limbs, the ISL classification was stage 0 in 13, stage I in 21, stage IIa in nine, stage IIb in 13, and stage III in two. The study was approved by our institutional review board, and informed consent was obtained from all patients. Medical interview. All patients were interviewed regarding the presence or absence of subjective symptoms of edema in each lower limb. When no subjective symptom was present, the case was regarded as type 0. When the patient was aware of apparent edema due to subjective symptoms such as a strange sensation and a distended feeling, the case was regarded as type 1. Cases with intra-
day variation in which symptoms repeatedly remitted and exacerbated were also included in the type 1 category. ISL lymphedema staging.10 In the ISL classification, stage 0 refers to a latent or subclinical condition where swelling is not evident despite impaired lymph transport. This stage may exist for months or years before overt edema occurs (stages I-III). Stage I represents an early accumulation of fluid that is relatively high in protein content (eg, in comparison with “venous” edema) and subsides with limb elevation. Pitting may occur. Stage IIa signifies that limb elevation alone rarely reduces tissue swelling and pitting is manifest. In stage IIb, the limb may or may not pit as tissue fibrosis supervenes. Stage III encompasses lymphostatic elephantiasis where pitting is absent and trophic skin changes such as acanthosis, fat deposits, and warty overgrowths develop. Lymphoscintigraphy. A Tc-99m-labeled nanocolloid was injected subcutaneously (w20 MBq in 0.1 mL per limb) into the dorsum of the first web space of the foot using a 1-mL syringe and a 27-gauge needle. Penetration of the needle into a blood vessel was excluded by careful aspiration before injection. Massage, warm compresses, and lower limb elevation were not permitted after injection. Half-body anterior and posterior images from the upper abdomen to the toes were obtained with a large field-ofview gamma camera, immediately and at 15, 30, 60, and 90 minutes after tracer injection. Staging based on lymphoscintigraphy was performed using the classification proposed by Maekawa et al14: no abnormal findings (type 1), a dermal backflow pattern (DB) above the knee (type 2), DB from above to below the knee (type 3), DB only below the knee (type 4), and no enhancement (type 5). ICG lymphography. ICG lymphography was performed within 3 months after lymphoscintigraphy. ICG (0.2 mL, Diagnogreen 0.5%; Daiichi Pharmaceutical, Tokyo, Japan) was injected intracutaneously into the bilateral first interdigits. Imaging was performed using a PDE system (Hamamatsu Photonics, Hamamatsu, Japan). Vivid dynamic images of superficial lymphatic flow were obtained within a few minutes after the injection. In this method, the skin surface is illuminated with near-infrared light, and light emitted by ICG absorbed in lymph vessels is imaged using a charge coupled device camera to detect lymph flow in subcutaneous lymph vessels. For staging of lymphedema based on ICG lymphography, the classification proposed by Yamamoto et al was used18,19: normal lymphatic pattern (stage 0; Video A, available online only); abnormal findings, such as splash and stardust patterns, in the inguinal region only (stage 1); a stardust pattern above the knee, but normal lymph flow below the knee (stage 2); a stardust pattern in the inguinal region over the ankle, but normal lymph flow on the distal side from the ankle (stage 3); a stardust pattern spread to the toes (stage 4); and a diffuse pattern (stage 5; Video B, available online only). Statistical analysis. The sensitivity and specificity of lymphoscintigraphy and ICG lymphography were determined based on the findings of the clinical evaluation. If patients have a complaint of pain or an uncomfortable
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feeling in their limbs, we determined this to be positive, because they are thought to be subclinical lymphedema. Receiver-operating characteristic curves were prepared and the area under the curve (AUC) was compared for the two methods. Statistical analysis was performed using JMP software (SAS Institute, Cary, NC). RESULTS A summary of the 29 cases (58 limbs) examined in the study is shown in the Table. All procedures were completed without problems in all patients. Based on the interview, five and 53 limbs were classified as types 0 and 1, respectively; on lymphoscintigraphy, 34, 6, 11, 6, and 1 limb were classified as types 1, 2, 3, 4, and 5, respectively; and on ICG lymphography, 10, 13, 4, 16, 6, and 9 limbs were staged as 0, 1, 2, 3, 4, and 5, respectively. The correlation between lymphoscintigraphy, ICG lymphography, or ISL staging is shown in Fig 1. In lymphoscintigraphy, 34 out of 58 limbs were classified as grade 0, which represent normal findings (Fig 2, a and d). On the other hand, in ICG lymphography, only nine limbs were classified as grade 1, which represents normal (Fig 2, b and e). This difference may show the advantage of ICG lymphography in diagnosing early-stage lymphedema. The sensitivity and specificity of lymphscintigraphy was 0.45 and 1.00, respectively; of ICG lymphography was
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0.89 and 0.80, respectively. The AUC on receiveroperating characteristic analysis of the 58 limbs was 0.72642 for lymphoscintigraphy (Fig 2, a), 0.90943 for ICG lymphography (Fig 2, b), and 0.9245 for ISL staging (Fig 2, c). In the 34 limbs with early lymphedema (ISL stages 0-1), the AUC was 0.55882 for lymphoscintigraphy (Fig 2, d), 0.81471 for ICG lymphography (Fig 2, e), and 0.8088 for ISL staging (Fig 2, f). To illustrate these results further, we present findings from one normal case (not included in our series) and two representative lymphedema cases. The patient in case 0 was a 61-year-old woman who had a complaint of bilateral lower limb edema. She had no medical history. We performed lymphscintigraphy and ICG lymphography, and no abnormal findings could be seen (Fig 3). The patient in case 1 was a 52-year-old woman who underwent hysterectomy and lymph node dissection for cervical cancer 2 years ago. Discomfort of the medial sides of the bilateral thighs had appeared starting from the right lower limb 6 months ago and slowly aggravated. Conservative treatment with lymph massage was used immediately after the appearance of the subjective symptom, but the symptom was not remitted. A physical examination revealed no enlargement of the circumference of the bilateral lower limbs. Pitting edema was sometimes noted on
Fig 2. Receiver-operating characteristic curve of indocyanine green (ICG) lymphography, lymphoscintigraphy, and International Society of Lymphology (ISL) classification. a, ICG lymphography, (b) lymphoscintigraphy, (c) ISL classification, (d) ICG lymphography, (e) lymphoscintigraphy, and (f) ISL classification in early-stage lymphedema, respecively.
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the anterior surface of the bilateral lower thigh in the afternoon. On lymphoscintigraphy, there was no dermal backflow in the bilateral lower limbs (right limb: type 1, left limb: type 1; Fig 4, a). In ICG lymphography (right limb: stage 1; left limb: stage 1; Fig 4, b-e), several vivid dynamic images of a superficial lymphatic linear pattern, indicating normal lymphatic flow, in the bilateral dorsi of the feet and lower and distal thigh areas were obtained within a few minutes after injection (Fig 4, d and e). A stardust pattern indicating mildly damaged lymph flow was present in the bilateral proximal thighs and lower abdomen area (Fig 4, c). The patient in case 11 was a 62-year-old Japanese woman who had noted worsening edema in her right lower limb for about 6 years. She had previously undergone extended hysterectomy with lymph node dissection for cervical cancer without radiation therapy. Despite constant and strong compressive therapy with an elastic stocking for 5 years, the edema gradually progressed, and cellulitis in her right thigh recurred every 2 to 3 months. A physical examination revealed enlargement of the circumference
of the right lower extremity of 4 cm at the thigh, 3 cm at the knee, 3 cm at the calf, and 2 cm at the ankle compared with the left extremity. On lymphoscintigraphy, dermal backflow was noted in only the right lower thigh (right limb: type 5; left limb: type 1; Fig 5, a). In ICG lymphography, several vivid dynamic images of a superficial lymphatic linear pattern, indicating normal lymphatic flow, in the right lateral knee and left lower limb were obtained within a few minutes after injection (right limb: stage 5; left limb: stage 1; Figs 5, b and c, and 6). A splash pattern indicating pressure elevation in the lymph network was present in the right dorsum of the foot and bilateral groin (Fig 6, b). A stardust pattern indicating mildly damaged lymph flow was present in the right thigh (Fig 6, c), and a diffuse pattern indicating severely damaged lymph flow was observed in the right lower thigh (Fig 6, d). DISCUSSION We compared the accuracy of ICG lymphography and lymphoscintigraphy in patients with secondary lymphedema of the lower limbs and found that the ICG method was
Fig 3. Case 0. a, Lymphoscintigraphy. The lymph vessels were normal in the bilateral legs. b, Physical findings and indocyanine green (ICG) lymphography patterns. Physically, there was no difference in the circumferences of the bilateral legs. In ICG lymphography, a linear pattern (LP) was found in the bilateral lower limbs. c, ICG lymphography of the left lower limb, showing an LP. LN, Lymph node.
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Fig 4. Case 1. a, Lymphoscintigraphy. The lymph vessels were normal in the bilateral legs. b, Physical findings and indocyanine green (ICG) lymphography patterns. Physically, there was no difference in the circumferences of the bilateral legs. In ICG lymphography, a stardust pattern (SD) was found in the proximal medial regions of the bilateral thighs and lower abdominal region. A linear pattern (LP) was observed in the bilateral distal thighs to the toes. c, ICG lymphography of the lower abdominal and pubic area and proximal thigh region, showing a marked SD. d, ICG lymphography showing an LP in the medial crus. e, ICG lymphography showing an LP in the bilateral dorsi of the feet and ankle joints.
Fig 5. Case 11. a, Lymphoscintigraphy. Dermal backflow patterns were noted mainly in the medial region of the right crus. Lymph vessels in the left leg were normal. b, Physical findings and indocyanine green (ICG) lymphography patterns. b and c, In ICG lymphography, a stardust pattern (SD) was found in the bilateral inguinal regions. In the right leg, an SD was observed in the medial thigh and a linear pattern (LP) in the knee. A splash pattern (SP) was present in the dorsum of the right foot. In the left leg, an LP was present distal from the inguinal region. DP, Diffuse pattern.
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Fig 6. Indocyanine green (ICG) lymphography findings in case 11. a, A stardust pattern in the medial region of the right thigh. b, A diffuse pattern in the medial region of the right crus. c, A splash pattern in the dorsum of the right foot and ankle joint. d, A linear pattern in the dorsum of the left foot and ankle joint.
more accurate than lymphoscintigraphy. The sensitivity and specificity of lymphoscintigraphy were both low for early diagnosis of lymphedema (0.11 and 0.00, respectively), whereas those of ICG lymphography were very high (0.76 and 0.80, respectively), showing the particular utility of this method for early diagnosis. Both lymphoscintigraphy and ICG lymphgraphy show lymphatic flow or dermal backflow if there is lymphatic impairment. The advantages of ICG lymphography compared with lymphoscintigraphy are the absence of radiation exposure, the short time required for the test, usefulness for lymphedema clinical stratification, and the real-time visualization of lymph flow. Also, since ICG lymphography can be used during surgery, it is very useful for searching for lymph vessels suitable for lymphaticovenous anastomosis. Furthermore, since images in lymphoscintigraphy can be acquired in the anteroposterior direction only, regions likely to retain lymph in the early stage, such as the medial region of the thigh, anatomically
overlap healthy collecting lymph vessels in these regions, making visualization of mild dermal backflow patterns difficult. In contrast, the camera position can be freely changed in ICG lymphography, enabling acquisition in all directions. Therefore, the whole affected limb can be examined, and this may be the cause of the greater accuracy of ICG lymphography for early diagnosis of lymphedema. However, ICG lymphography has the disadvantage that only regions at a depth up to 2 cm from the skin can be observed, whereas lymphatic function can be observed in all layers using lymphoscintigraphy. Therefore, more detailed evaluation of lymphatic function and identification of the location of lymph vessels are possible using ICG lymphography and lymphoscintigraphy in combination. Abnormalities were detected by ICG lymphography in patients with no subjective symptoms. Burnand et al observed abnormality in the opposite lower limb in a patient with unilateral lower limb lymphedema with no subjective symptoms and diagnosed this condition as lymph vascular dysfunction.20 Yamamoto et al found that abnormal findings may be observed on ICG lymphography in the absence of subjective symptoms of edema and suggested that this indicates a very early finding of lymphedema.18-21 In gynecological cancer treatment, pelvic or para-aortic lymph node dissection is performed, and it is likely that lymph vascular dysfunction will occur on the ipsilateral side, even though lymphedema is currently present only on the unilateral side.22-25 The findings of abnormalities in ICG lymphography in the absence of subjective symptoms in our patients also suggests the presence of early lymphedema. However, the possibility of false-positive findings cannot be ruled out, and periodic course observation is required following abnormal findings on ICG lymphography. We note that the ICG method itself may be appropriate for continuous observation because of the absence of radiation exposure.16-19 We also found that cases in which patients described a strange sensation and pain without apparent edema were lymphedema-positive. It is clear that these symptoms are associated with lymphedema, and avoidance of overlooking such symptoms may contribute to the early diagnosis of lymphedema. Indication of surgical treatment for lymphedema can be decided when the abnormal pattern in ICG lymphgraphy expands or proceeds to the next stage. Since the subjects were limited to patients with secondary lymphedema after surgery for gynecological cancer, we used classifications that reflected the progression of lymphedema severity based on advancement from proximal to distal regions for grading abnormal findings on lymphoscintigraphy and ICG lymphography.14,18,19 However, this approach does not apply to primary lymphedema, in which specific findings are observed in many cases. Therefore, a further investigation is necessary for cases of primary lymphedema. However, within this limitation, we conclude that ICG lymphography is more accurate than lymphoscintigraphy for diagnosis of lymphedema and that the ICG method is particularly useful for diagnosis of early lymphedema.
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Also, the correlation between the results of surgery and the ICG lymphography is another problem. More research is needed. In conclusion, ICG lymphography was more accurate than lymphoscintigraphy for detecting lymphedema and was particularly useful for the diagnosis of early lymphedema. This is clinically important since early diagnosis may permit curative treatment of lymphedema.
11.
12. 13.
The authors are grateful to Dr Akio Hirota (Hirota Internal Medicine Clinic) for his advice. 14.
AUTHOR CONTRIBUTIONS Conception and design: MM, HH, MN, TT, TI Analysis and interpretation: MM, HH, MN, TT, TI, NM, TK Data collection: MM, HH Writing the article: MM, HH Critical revision of the article: MM Final approval of the article: MM Statistical analysis: HO Obtaining funding: MM Overall responsibility: MM MM and HH contributed equally to this work. REFERENCES 1. Raju S, Furrh JB 4th, Neglen P. Diagnosis and treatment of venous lymphedema. J Vasc Surg 2012;55:141-9. 2. Tam EK, Shen L, Munneke JR, Ackerson LM, Partee PN, Somkin CP, et al. Clinician awareness and knowledge of breast cancer-related lymphedema in a large, integrated health care delivery setting. Breast Cancer Res Treat 2012;131:1029-38. 3. Mehrara BJ, Zampell JC, Suami H, Chang DW. Surgical management of lymphedema: past, present, and future. Lymphat Res Biol 2011;9:159-67. 4. Mukenge SM, Catena M, Negrini D, Ratti F, Moriondo A, Briganti A, et al. Assessment and follow-up of patency after lymphovenous microsurgery for treatment of secondary lymphedema in external male genital organs. Eur Urol 2011;60:1114-9. 5. 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. 6. Campisi C, Bellini C, Campisi C, Accogli S, Bonioli E, Boccardo F. Microsurgery for lymphedema: clinical research and long-term results. Microsurgery 2010;30:256-60. 7. Francesco B, Corrado C, Giuseppe M, Emanuela B, Chiara B, Francesco P, et al. Prevention of lymphatic injuries in surgery. Microsurgery 2010;30:261-5. 8. Boccardo FM, Ansaldi F, Bellini C, Accogli S, Taddei G, Murdaca G, et al. Prospective evaluation of a prevention protocol for lymphedema following surgery for breast cancer. Lymphology 2009;42:1-9; Erratum in: Lymphology 2009;42:149. 9. Mihara M, Murai N, Hayashi Y, Hara H, Iida T, Narushima M, et al. Using indocyanine green fluorescent lymphography and lymphaticvenous anastomosis for cancer-related lymphedema. Ann Vasc Surg 2012;26:278.e1-6. 10. Bernas MJ, Witte CL, Witte MH, International Society of Lymphology Executive Committee. The diagnosis and treatment of peripheral
15. 16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
Mihara et al 201
lymphedema: draft revision of the 1995 Consensus Document of the International Society of Lymphology Executive Committee for discussion at the September 3-7, 2001, XVIII International Congress of Lymphology in Genoa, Italy. Lymphology 2001;34:84-91. Hormes JM, Bryan C, Lytle LA, Gross CR, Ahmed RL, Troxel AB, et al. Impact of lymphedema and arm symptoms on quality of life in breast cancer survivors. Lymphology 2010;43:1-13. Lockwood-Rayermann S. Lymphedema in gynecologic cancer survivors: an area for exploration? Cancer Nurs 2007;30:E11-8. de Rezende LF, Pedras FV, Ramos CD, Gurgel MS. Evaluation of lymphatic compensation by lymphoscintigraphy in the postoperative period of breast cancer surgery with axillary dissection. Tumori 2011;97:309-15. Maegawa J, Mikami T, Yamamoto Y, Satake T, Kobayashi S. Types of lymphoscintigraphy and indications for lymphaticovenous anastomosis. Microsurgery 2010;30:437-42. Beveridge N, Allen L, Rogers K. Lymphoscintigraphy in the diagnosis of lymphangiomatosis. Clin Nucl Med 2010;35:579-82. Ogata F, Narushima M, Mihara M, Azuma R, Morimoto Y, Koshima I. Intraoperative lymphography using indocyanine green dye for near-infrared fluorescence labeling in lymphedema. Ann Plast Surg 2007;59:180-4. Ogata F, Azuma R, Kikuchi M, Koshima I, Morimoto Y. Novel lymphography using indocyanine green dye for near-infrared fluorescence labeling. Ann Plast Surg 2007;58:652-5. Yamamoto T, Matsuda N, Doi K, Oshima A, Yoshimatsu H, Todokoro T, et al. 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. Plast Reconstr Surg 2011;128:314e-21e. Yamamoto T, Narushima M, Doi K, Oshima A, Ogata F, Mihara M, et al. Characteristic indocyanine green lymphography findings in lower extremity lymphedema: the generation of a novel lymphedema severity staging system using dermal backflow patterns. Plast Reconstr Surg 2011;127:1979-86. Suami H, Chang DW, Yamada K, Kimata Y. Use of indocyanine green fluorescent lymphography for evaluating dynamic lymphatic status. Plast Reconstr Surg 2011;127:74e-6e. Furukawa H, Osawa M, Saito A, Hayashi T, Funayama E, Oyama A, et al. Microsurgical lymphaticovenous implantation targeting dermal lymphatic backflow using indocyanine green fluorescence lymphography in the treatment of postmastectomy lymphedema. Plast Reconstr Surg 2011;127:1804-11. Burnand KM, Glass DM, Mortimer PS, Peters AM. Lymphatic dysfunction in the apparently clinically normal contralateral limbs of patients with unilateral lower limb swelling. Clin Nucl Med 2012;37: 9-13. Todo Y, Yamamoto R, Minobe S, Suzuki Y, Takeshi U, Nakatani M, et al. Risk factors for postoperative lower-extremity lymphedema in endometrial cancer survivors who had treatment including lymphadenectomy. Gynecol Oncol 2010;119:60-4. Gould N, Kamelle S, Tillmanns T, Scribner D, Gold M, Walker J, et al. Predictors of complications after inguinal lymphadenectomy. Gynecol Oncol 2001;82:329-32. Kridelka FJ, Berg DO, Neuman M, Edwards LS, Robertson G, Grant PT, et al. Adjuvant small field pelvic radiation for patients with high risk, stage IB lymph node negative cervix carcinoma after radical hysterectomy and pelvic lymph node dissection. A pilot study. Cancer 1999;86:2059-65.
Submitted Jan 25, 2012; accepted Jul 15, 2012.
Additional material for this article may be found online at www.jvsvenous.org.