Lymphoedema of the extremities is a chronic, debilitating disease. Early diagnosis and treatment are crucial to reduce the risk of progression and the development of complications. Patients requiring evaluation for extremity lymphoedema can be divided into two groups, primary and secondary lymphoedema, with differing examination objectives in each group. Patients with primary lymphoedema are frequently misdiagnosed and may suffer a long time before receiving a specific examination. Proper examination should be conducted to detect primary lymphoedema when it is first suspected. In patients with secondary lymphoedema, it is not very difficult to diagnose lymphoedema from the medical history and physical findings, although it is necessary to determine the underlying cause of the extremity oedema and to exclude any other aetiologies. In typical patients following lymph node dissection, symptoms start in areas close to the operated region: the groin and proximal femur region in the lower extremity and the axilla and proximal humerus in the upper extremity.
Journal of Plastic, Reconstructive & Aesthetic Surgery (2013) 66, 792e798 Comparison of lymphoscintigraphy and indocyanine green lymphography for the diagnosis of extremity lymphoedema Shinsuke Akita a,*, Nobuyuki Mitsukawa a, Toshiki Kazama b, Motone Kuriyama c, Yoshitaka Kubota a, Naoko Omori a, Tomoe Koizumi a, Kentaro Kosaka a, Takashi Uno b, Kaneshige Satoh a a Department of Plastic, Reconstructive and Aesthetic Surgery, Chiba University Graduate School of Medicine, Chiba, Japan Department of Diagnostic Radiology and Radiation Oncology, Chiba University Graduate School of Medicine, Chiba, Japan c Department of Plastic and Reconstructive Surgery in Kochi Medical School Hospital, Nankoku, Japan b Received 20 January 2013; accepted 18 February 2013 KEYWORDS Lymphoedema; Lymphoscintigraphy; Indocyanine green lymphography Summary Background: Lymphoscintigraphy is the gold-standard examination for extremity lymphoedema Indocyanine green lymphography may be useful for diagnosis as well We compared the utility of these two examination methods for patients with suspected extremity lymphoedema and for those in whom surgical treatment of lymphoedema was under consideration Methods: A total of 169 extremities with lymphoedema secondary to lymph node dissection and 65 extremities with idiopathic oedema (suspected primary lymphoedema) were evaluated; the utility of indocyanine green lymphography for diagnosis was compared with lymphoscintigraphy Regression analysis between lymphoscintigraphy type and indocyanine green lymphography stage was conducted in the secondary lymphoedema group Results: In secondary oedema, the sensitivity of indocyanine green lymphography, compared with lymphoscintigraphy, was 0.972, the specificity was 0.548 and the accuracy was 0.816 When patients with lymphoscintigraphy type I and indocyanine green lymphography stage I were regarded as negative, the sensitivity of the indocyanine green lymphography was 0.978, the specificity was 0.925 and the accuracy was 0.953 There was a significant positive correlation between the lymphoscintigraphy type and the indocyanine green lymphography stage In idiopathic oedema, the sensitivity of indocyanine green lymphography was 0.974, the specificity was 0.778 and the accuracy was 0.892 Conclusion: In secondary lymphoedema, earlier and less severe dysfunction could be detected by indocyanine green lymphography Indocyanine green lymphography is recommended to determine patients’ suitability for lymphaticovenular anastomosis, because the diagnostic * Corresponding author Tel.: ỵ81 43 222 7171; fax: ỵ81 43 226 2316 E-mail address: sakita-chiba@umin.ac.jp (S Akita) 1748-6815/$ - see front matter ª 2013 British Association of Plastic, Reconstructive and Aesthetic Surgeons Published by Elsevier Ltd All rights reserved http://dx.doi.org/10.1016/j.bjps.2013.02.023 Comparison of lymphoscintigraphy and indocyanine green lymphography 793 ability of the test and its evaluation capability for disease severity is similar to lymphoscintigraphy but with less invasiveness and a lower cost To detect primary lymphoedema, indocyanine green lymphography should be used first as a screening examination; when the results are positive, lymphoscintigraphy is useful to obtain further information ª 2013 British Association of Plastic, Reconstructive and Aesthetic Surgeons Published by Elsevier Ltd All rights reserved Lymphoedema of the extremities is a chronic, debilitating disease Early diagnosis and treatment are crucial to reduce the risk of progression and the development of complications.1,2 Patients requiring evaluation for extremity lymphoedema can be divided into two groups, primary and secondary lymphoedema, with differing examination objectives in each group Patients with primary lymphoedema are frequently misdiagnosed and may suffer a long time before receiving a specific examination Proper examination should be conducted to detect primary lymphoedema when it is first suspected In patients with secondary lymphoedema, it is not very difficult to diagnose lymphoedema from the medical history and physical findings, although it is necessary to determine the underlying cause of the extremity oedema and to exclude any other aetiologies In typical patients following lymph node dissection, symptoms start in areas close to the operated region: the groin and proximal femur region in the lower extremity and the axilla and proximal humerus in the upper extremity.3,4 The objective of conducting oedema examinations in these patients is mainly to grade the severity of the lymphoedema and to decide whether treatments such as reconstructive surgery for lymphatic function are indicated.5e11 Of the available lymphatic system-examination methods, the best-suited method for each patient should be selected Lymphoscintigraphy was first introduced in 1953 and has been widely used to evaluate the lymphatic system.5e8,11e17 It is the primary imaging modality used to definitively diagnose patients with suspected extremity lymphoedema and is considered the gold standard for the diagnosis of primary lymphoedema, distinguishing this condition from idiopathic extremity oedema of other causes, and for the diagnosis and categorisation of secondary lymphoedema Indocyanine green lymphography was first introduced in 2007; it has lower costs and is less invasive than lymphoscintigraphy.4,9,10,18e20 We compared the utility of these two examination methods for patients with suspected extremity lymphoedema and for those in whom surgical treatment of lymphoedema was under consideration Patients and methods A retrospective study was conducted in 134 consecutive patients who underwent both lymphoscintigraphy and indocyanine green lymphography to investigate extremity oedema at Chiba University Hospital between August 2010 and March 2012 The study protocol was approved by the institutional review board and written informed consent was obtained from all subjects In all patients, both extremities, whether involved or uninvolved, were injected and imaged simultaneously Patients were divided into a secondary group and an idiopathic group, based on whether they had secondary lymphoedema after lymph node dissection or were suspected of primary lymphoedema when other possible causes had been excluded Patients with lymphoedema secondary to filariasis, infection or trauma were not included in the study A total of 169 limbs in 95 secondary patients and 65 limbs in 39 idiopathic patients were included in the study Lymphoscintigraphy was performed by subcutaneous injection of a small amount (1.0 ml, 200 MBq) of technetium-99m-labelled human serum albumin Injections were given bilaterally and simultaneously, in the first web spaces of the feet or hands Once this was accomplished, patients were asked to walk or to massage the injection site for 15 At 15 and 60 post-injection, whole body and spot imaging were acquired using a computerised gamma camera If tracer migration was not observed after 60 min, imaging was acquired again at 120 post-injection No consensus exists regarding the criteria for interpretation of lymphoscintigraphy results Although several attempts at improving objective interpretation through quantification of lymphatic function have been published, no general consensus has been reached to date.13,15,21,22 Infante et al evaluated different scintigraphic patterns17 and concluded that a high diagnostic yield is achieved by considering dermal backflow patterns and asymmetry in inguinal/axillary nodes; they reported an accuracy of 92.6% using these considerations The absence of tracer migration has a specificity and a positive predictive value (PPV) of 100%, but evaluation of intermediate lymph nodes and for the presence of collateral pathways contributes little to the diagnostic yield In the present study, lymphoscintigraphy was considered positive for lymphoedema when dermal backflow, absent or decreased inguinal/axillary lymph nodes or the absence of tracer migration was recorded Intermediate lymph nodes and the presence of collateral pathways were excluded from the diagnostic criteria Maegawa et al categorised patients with secondary lymphoedema into five types based on lymphoscintigraphy findings and used this distinction to determine whether lymphaticovenular anastomosis was indicated.7,8 The findings in the present study were categorised into six scintigraphy types, as described in Table (Figure 1) Indocyanine green lymphography was performed as follows: 0.3 ml of indocyanine green was injected subcutaneously into the bilateral first web spaces of the feet One hour after injection, circumferential fluorescent images of lymphatic drainage channels were obtained using a photodynamic eye infrared camera system (Hamamatsu Photonics K.K., Hamamatsu, Japan) Yamamoto et al categorised indocyanine green lymphography findings into a normal linear 794 S Akita et al Table dema Lymphoscintigraphy type: secondary lymphoe- Type Description Inguinal/axillary lymph nodes stain normally; no dermal backflow pattern is seen The number of visible inguinal/axillary lymph nodes is reduced Few or no inguinal/axillary lymph nodes are seen; dermal backflow is seen in the thigh/ upper arm No inguinal/axillary lymph nodes are detected; dermal backflow is seen in the thigh and leg/ upper arm and forearm Dermal backflow and lymph stasis are seen in the leg/forearm No dermal backflow is seen; no tracer migration is seen I II III IV V pattern and three abnormal dermal backflow patterns.4,9,10 Typically, the findings change from a normal linear pattern to a splash pattern, followed by a stardust pattern and a diffuse pattern as the severity of lymphoedema increases (Figure 2) Even in obese patients, it is usually possible to observe inguinal and axillary lymph nodes within 15 after injection when the lymphatic function is normal In this study, indocyanine green lymphography was considered positive for lymphoedema when the dermal backflow pattern, absent or decreased inguinal/axillary lymph nodes or the absence of indocyanine green dye migration was recorded at 60 and 120 after injection Yamamoto et al categorised secondary lymphoedema into five stages based on indocyanine green lymphography findings and demonstrated that the stage of indocyanine green lymphography correlates with clinical severity.9,10 In this study, indocyanine green lymphography was classified based on these categories, as described in Table Figure Indocyanine green lymphography findings are categorized into patterns Dermal backflow patterns generally progress from splash to stardust to diffuse as the severity of the lymphatic disorder increases To evaluate the utility of indocyanine green lymphography, its results were compared with those of the gold standard, lymphoscintigraphy Using the assumption that the sensitivity and specificity of lymphoscintigraphy is 1.00, the sensitivity, specificity, PPV, negative predictive value (NPV), positive likelihood ratio, negative likelihood ratio and accuracy of indocyanine green lymphography were calculated These values were calculated separately for the secondary group and the idiopathic group Regression analysis between lymphoscintigraphy type (Table 1) and indocyanine green lymphography stage (Table 2) was performed in the secondary group to assess the correlation of both examination findings between categories The results of the gold-standard test were calculated from a  contingency table Accuracy was defined as the ratio of (number of true positives ỵ number of true negatives) to (number of true positives ỵ number of false positives ỵ number of true negatives ỵ number of false negatives) Statistical analysis of the regression results was performed using the Statistical Package for the Social Sciences (SPSS), version 20 (IBM SPSS Inc., Chicago, IL, USA) Lymphoscintigraphy type was regarded as the dependent variable and indocyanine green lymphography stage was regarded as the independent variable A p-value of