- Email: [email protected]
Proximal and distal patterns: Different spreading patterns of indocyanine green lymphography in secondary lower extremity lymphedema
Accepted Manuscript Proximal and Distal Patterns: Different Spreading Patterns of Indocyanine Green Lymphography in Secondary Lower Extremity Lymphedema Kensuke Tashiro, M.D., Shuji Yamashita, M.D., Takafumi Saito, M.D., Takuya Iida, M.D., Isao Koshima, M.D. PII:
S1748-6815(15)00526-4
DOI:
10.1016/j.bjps.2015.10.042
Reference:
PRAS 4817
To appear in:
Journal of Plastic, Reconstructive & Aesthetic Surgery
Received Date: 18 August 2015 Revised Date:
23 October 2015
Accepted Date: 25 October 2015
Please cite this article as: Tashiro K, Yamashita S, Saito T, Iida T, Koshima I, Proximal and Distal Patterns: Different Spreading Patterns of Indocyanine Green Lymphography in Secondary Lower Extremity Lymphedema, British Journal of Plastic Surgery (2015), doi: 10.1016/j.bjps.2015.10.042. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
Title: Proximal and Distal Patterns: Different Spreading Patterns of Indocyanine Green
RI PT
Lymphography in Secondary Lower Extremity Lymphedema
Authors:
Kensuke Tashiro M.D., Shuji Yamashita M.D., Takafumi Saito M.D., Takuya Iida M.D.,
SC
Isao Koshima M.D.
Affiliation:
Tokyo, Japan
Corresponding Author: Kensuke Tashiro, M.D.
EP
Assistant professor
TE D
Financial Disclosure: None
M AN U
Department of Plastic and Reconstructive Surgery, University of Tokyo
Department of Plastic and Reconstructive Surgery, Graduate School of Medicine,
AC C
University of Tokyo, 7-3-1, Hongo, Bunkyo-ku Tokyo, Japan, 113-8655 Phone: 81-3-3815-5411 Fax: 81-3-5800-6929 E-mail: [email protected]
1
ACCEPTED MANUSCRIPT
Abstract [Background] As clinical evaluation of secondary lymphedema of the leg, indocyanine green (ICG)
RI PT
lymphographic assessment has been established its usefulness. In this study, we analyzed the ICG findings of patients with secondary lymphedema of the leg, focusing on the location and spreading pattern of dermal backflow (DBF).
SC
[Methods]
We investigated ICG findings of 90 patients with secondary lymphedema of the leg
M AN U
following malignant cancer resection between April 2013 and June 2015. The patients comprised 88 women and 2 men, and ICG lymphography was performed 12 to 24 hours after the injection.
TE D
[Results]
In 64 of the 90 patients, ICG lymphographic DBF was evident from the proximal region of the leg, and this type was termed the proximal pattern. In 18 of the 90 patients, DBF
AC C
pattern.
EP
appeared mainly in the distal part of the leg, and this type was termed the distal
[Conclusions]
In proximal pattern, the ICG injected into the distal part of the leg propelled to the proximal part of the leg, but an obstruction after lymphadenectomy caused ICG pooling to appear first on the proximal side. In distal pattern, hypoplasia of the lymphatic system of the leg may have already been present, and lymph node dissection might be only the trigger for the development of lymphedema. This classification may reflect the pumping function and preexisted hypoplasty of the lymphatic vessels, and provides a 2
ACCEPTED MANUSCRIPT
novel approach for the pathological evaluation of lymphedema. Patients of proximal pattern in ICG lymphography may be good indication for lymphatico-venous
AC C
EP
TE D
M AN U
SC
RI PT
anastomosis.
3
ACCEPTED MANUSCRIPT
Introduction Lymphedema occurs when lymph accumulates in the subcutaneous interstitium. The
RI PT
accumulation of protein-rich lymph causes inflammation, adipose tissue hypertrophy, and fibrosis, which not only causes cosmetic problems but also reduces mobility and function.1 As the condition becomes more severe, cellulitis often develops, which in the worst-case scenario can result in the development of fatal lymphangiosarcoma.
SC
Lymphedema is classified as primary or secondary depending on the cause: the former is believed to be due to lymphatic vessel hypoplasia, and the latter owing to obstruction
M AN U
of the central lymphatic system because of infection, cancer surgery, radiotherapy, or other causes.
Lymphedema is treated either surgically or conservatively. Surgery is carried out with the aim either of removing edematous tissue or of restoring lymphatic vessel function.
TE D
In the former case, fat resection or liposuction may be used, and in the latter, lymphaticovenous anastomosis (LVA) or lymph node transfer may be performed. 2,3,4 The methods commonly used to assess the severity of lymphedema include
EP
lymphoscintigraphy, magnetic resonance (MR) lymphography, and indocyanine green (ICG) lymphography. Lymphoscintigraphy has the advantage of providing wide-ranging
AC C
images of the entire leg, but is less useful for detailed evaluation. 5,6 MR lymphography similarly enables the assessment of the entire affected limb without the need for radiation exposure or drug administration, but does not allow lymphatic vessel function to be monitored in real time. 7 ICG lymphography enables the real-time assessment of lymphatic vessel function and can be used in lymphatic vessel surgery. It is minimally invasive, and accurately reflects the severity of lymphedema. 8,9,10 ICG lymphography has been used previously to assess the severity of lymphedema. 8,9,10 In secondary lymphedema of the leg following cancer surgery, dermal backflow (DBF) 4
ACCEPTED MANUSCRIPT
pattern occurs in the groin initially, and this descends to the thigh and lower leg; the DBF pattern may also change in tone to stardust or diffuse. In this study, we analyzed the ICG findings of patients with secondary lymphedema of the leg, and found that the
RI PT
findings can be broadly divided into two types according to the location of DBF. We describe these as proximal and distal patterns. This classification reflects the pumping function of the lymphatic vessels, and provides a novel approach for the pathological evaluation of lymphedema. It may also be useful as an index for predicting the
SC
effectiveness of LVA.
M AN U
Patients and Methods
We investigated ICG findings of 90 patients with secondary lymphedema of the leg following malignant cancer resection between April 2013 and June 2015. This study was approved by the Institutional Review Board of the University of Tokyo Hospital,
TE D
and was carried out retrospectively. Detailed patient information, including etiology, is listed in Table 1. The mean age was 59 years, and the mean duration of lymphedema was 4 years. The patients comprised 88 women and 2 men, with a mean body mass
EP
index (BMI) of 24.2. The underlying disease was cervical cancer in 46 cases, uterine cancer in 28, ovarian cancer in 10, and prostate cancer, penile cancer, colorectal cancer,
AC C
uterine sarcoma, Paget’s disease of the vulva, and malignant lymphoma in 1 case each. Radiotherapy was administered in 37 cases, and 65 patients had a history of cellulitis. In terms of the International Society of Lymphology (ISL) staging, 28 legs were Stage 0, 29 Stage 1, 93 Stage 2, and 30 Stage 3. ICG lymphography was performed as follows: 0.2 ml of ICG (Diagnogreen 0.25%; Daiichi Pharmaceutical, Tokyo, Japan) was injected subcutaneously into both lower extremities at the first web space of the foot and the lateral border of the Achilles tendon. Imaging was performed using a Photodynamic Eye (Hamamatsu Photonics, 5
ACCEPTED MANUSCRIPT
Hamamatsu, Japan) 12 to 24 hours after the injection. ICG lymphography images were recorded at a plateau phase of the lymphography. The diagnosis of ICG lymphographic patterns, proximal or distal patterns, were made by plastic surgeons trained for
RI PT
lymphedema treatment.
Results
A pattern of fluorescent contrast from the proximal region on ICG lymphography was
SC
evident in 64 of the 90 patients. This type was termed the proximal pattern. Cases in which DBF was evident in the entire leg were also classified as exhibiting the proximal
M AN U
pattern. When the proximal pattern was evident, the ICG injected into the distal part of the leg propelled to the proximal part of the leg, but an obstruction at a more central location caused ICG pooling to appear first on the proximal side. DBF that appeared first in the distal part of the leg on ICG lymphography was evident
TE D
in 18 of the 90 patients. This type was termed the distal pattern. In this pattern, the ICG injected into the distal part of the leg could not be propelled to the proximal region, meaning that ICG pooling only appeared in the distal region. Given the pathological
present.
EP
background, this suggested that lymphatic vessel hypoplasia already may have been
AC C
In 8 of the 90 patients, one leg exhibited the proximal pattern and the other the distal pattern on ICG lymphography. The leg that exhibited the proximal pattern, lymphatic vessel function was normal, and a central obstruction resulted in ICG pooling closer to the trunk, while the leg that exhibited the distal pattern, lymphatic vessel hypoplasia showed in ICG pooling at the distal end. Collateral lymphatic channels leading from lower abdomen to the axillary lymph nodes were present in 6 of the 64 patients who exhibited the proximal pattern. These represented the formation of lymph drainage channels as an attempt to drain the 6
ACCEPTED MANUSCRIPT
lymphatic fluid pooled in the lower abdomen and below, and reflected the vigorous pump function of the lymphatic vessels that produced the proximal pattern.
RI PT
Discussion We report a new classification of ICG lymphography findings for secondary lymphedema of the legs after cancer surgery. Yamamoto et al. previously have reported the use of ICG lymphography to assess the severity of secondary lymphedema of the
SC
legs after cancer surgery. 10 They found, that according to the progression of secondary lymphedema of the legs, the dermal backflow initially had a splash pattern in the groin,
M AN U
which gradually descended toward the foot until it extended throughout the entire leg. We analyzed ICG lymphography findings from 90 patients with secondary lymphedema of the legs, and showed that they could broadly be divided into two patterns: proximal and distal patterns.
TE D
In the proximal pattern, DBF initially appeared at the proximal end of the legs and gradually descended. In this pattern, ICG lymphography also frequently reveals DBF in the abdomen, and sometimes, in the genital region. It often exhibits a linear pattern of
EP
lymphatic ducts in the distal part of the leg, where lymphatic vessel function is usually normal. The pumping function of the lymphatic vessels is well maintained throughout
AC C
the leg, and ICG injected subcutaneously in the foot is propelled to the proximal part of the leg, but obstruction of the lymphatic vessels in the abdominal cavity causes lymphatic fluid to be retained in the abdomen or upper leg, resulting in the development of lymphedema. 11 In this proximal pattern, collateral lymphatic channel formation may occasionally be seen past the watershed of the umbilicus toward ipsilateral axillary lymph nodes. In this study, we observed collateral lymphatic vessels in 6 of 64 patients who exhibited the proximal pattern. These collateral lymphatic channels may have been formed because of 7
ACCEPTED MANUSCRIPT
the vigorous pumping function of the lymphatic vessels creating new drainage channels from lower abdomen to ipsilateral axillary lymph nodes. 12,13,14,15 In the distal pattern, DBF starts from the distal part of the leg. Fluorescence is not
RI PT
generally evident in the proximal part on ICG lymphography, indicating that the lymphatic system in the leg is not capable of propelling ICG upward. Hypoplasia of the lymphatic system of the leg may have already been present in such patients, and lymph node dissection was only the trigger for the development of lymphedema, with
SC
lymphatic system hypoplasia being the main cause. Underlying the distal pattern is thus latent lymphatic vessel hypoplasia, which is the main cause of primary
M AN U
lymphedema, and this is a different pathological mechanism compared to that involved in secondary lymphedema exhibiting the proximal pattern, which has a central obstruction of the lymphatic system as its basis.
Primary lymphedema is frequently triggered by mild trauma such as a sprain or
TE D
compression from a bandage. This tends to be more common from adolescence through to middle age. Although many aspects of the etiology of primary lymphedema remain unclear, lymphatic vessel hypoplasia is believed to be the underlying mechanism.
EP
Primary and secondary lymphedema exhibit different patterns on ICG lymphography. In light of our results in this study, some cases previously classified as secondary
AC C
lymphedema may actually be similar to primary lymphedema caused by lymphatic vessel hypoplasia.
The effectiveness of LVA is influenced by the condition of the lymphatic vessels. The stronger their pumping action, the greater the volume of lymphatic fluid that can be drained, causing improvement in lymphedema. Although LVA may greatly improve lymphedema with minimal invasiveness, there are no clear indication criteria, and it is ineffective in some cases.
16,17,18,19
Our results indicated that preoperative ICG
lymphography may enable the pumping function of the lymphatic vessels to be assessed, 8
ACCEPTED MANUSCRIPT
clarifying whether LVA is indicated. In patients who exhibit the proximal pattern, the underlying pumping function of the lymphatic vessels is well maintained, and LVA is more likely to be effective. In those who exhibit the distal pattern, however, the
RI PT
pumping function of the lymphatic vessels is already poor, and LVA may be relatively ineffective.
Our study indicated that the location of the appearance of DBF may be as important as its tone in ICG lymphography. This is because it provides an indication of the pumping
SC
ability of the lymphatic vessels, a function of smooth muscle.20 Our results also suggested that the condition of the lymphatic vessels may vary even within a single leg,
M AN U
indicating the diverse pathology of lymphedema. The use of ICG lymphography may clearly reveal the condition of the lymphatic vessels.
Conclusion
TE D
Secondary lymphedema can be classified into two types depending on the location of appearance of DBF on ICG lymphography. We categorize these as proximal and distal patterns. These may reflect the pumping function of the lymphatic vessels, and patients
EP
of proximal pattern in ICG lymphography may be good indication for LVA.
AC C
Funding: None declared.
Conflicts of Interest Statement: None declared.
References
1. Kerchner K, Fleischer A, Yosipovitch G. Lower extremity lymphedema update: pathophysiology, diagnosis, and treatment guidelines. J Am Acad Dermatol. 2008 Aug;59(2):324-31 2. Koshima I, Nanba Y, Tsutsui T, et al. Minimal invasive lymphaticovenular 9
ACCEPTED MANUSCRIPT
anastomosis under local anesthesia for leg lymphedema: is it effective for stage III and IV? Ann Plast Surg 2004; 53: 261-6. 3. Koshima I, Narushima M, Yamamoto Y, Mihara M, Iida T. Recent advancement on
RI PT
surgical treatments for lymphedema. Ann Vasc Dis. 2012;5(4):409-15. 4. Becker C, Assouad J, Riquet M, Hidden G. Postmastectomy lymphedema: long-term results following microsurgical lymph node transplantation. Ann Surg. 2006 Mar;243(3):313-5.
SC
5. Samuels LD. Lymphoscintigraphy. Lymphology. 1987 Mar;20(1):4-9.
6. Iimura T, Fukushima Y, Kumita S, Ogawa R, Hyakusoku H. Estimating Conditions
and
Lymphovenous
Anastomosis
M AN U
Lymphodynamic
Efficacy
Using
(99m)Tc-phytate Lymphoscintigraphy with SPECT-CT in Patients with Lower-limb Lymphedema. Plast Reconstr Surg Glob Open. 2015 Jun 5;3(5):e404. 7. Lu Q, Delproposto Z, Hu A, Tran C, Liu N, Li Y, Xu J, Bui D, Hu J. MR lymphography
TE D
of lymphatic vessels in lower extremity with gynecologic oncology-related lymphedema. PLoS One. 2012;7(11):e50319.
8. Ogata F, Azuma R, Kikuchi M, Koshima I, Morimoto Y. Novel lymphography using
EP
indocyanine green dye for near-infrared fluorescence labeling. Ann Plast Surg. 2007 Jun;58(6):652-5.
AC C
9. 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 Aug;59(2):180-4. 10. Yamamoto T, Narushima M, Doi K, Oshima A, Ogata F, Mihara M, Koshima I, Mundinger GS. 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 May;127(5):1979-86. 11. Gómez FM, Martínez-Rodrigo J, Martí-Bonmatí L, Santos E, Forner I, Lloret M, 10
ACCEPTED MANUSCRIPT
Pérez-Enguix D, García-Marcos R. Transnodal lymphangiography in the diagnosis and treatment of genital lymphedema. Cardiovasc Intervent Radiol. 2012 Dec;35(6):1488-91. 12. Sappey MPC (1874) Anatomie, physiologie, pathologie des vaisseaux lymphatiques
RI PT
consideres chez l’homme at les vertebres. Paris: A. Delahaye and E. Lecrosnier. 13. Suami H, Yamashita S, Soto-Miranda MA, Chang DW. Lymphatic territories (lymphosomes) in a canine: an animal model for investigation of postoperative lymphatic alterations. PLoS One. 2013 Jul 24;8(7):e69222.
SC
14. Bobbio P, Peracchia G, Pellegrino F (1962) Connessioni linfatiche presternali fra le regioni mammarie dei due lati. Ateneo Parmensa 33(supp.): 95–109.
M AN U
15. Tashiro K, Shibata T, Mito D, Ishiura R, Kato M, Yamashita S, Narushima M, Iida T, Koshima I. Indocyanine Green Lymphographic Signs of Lymphatic Collateral Formation in Lower Extremity Lymphedema after Cancer Resection. Annals of Plastic Surgery. In press.
TE D
16. Akita S, Mitsukawa N, Rikihisa N, Kubota Y, Omori N, Mitsuhashi A, Tate S, Shozu M, Satoh K. Early diagnosis and risk factors for lymphedema following lymph node dissection for gynecologic cancer. Plast Reconstr Surg. 2013 Feb;131(2):283-90.
EP
17. Tashiro K, Mihara M, Todokoro T, Narushima M, Yamamoto T, Iida T, Araki J, Iwamoto T, Koshima I. Christmas tree background for supermicrosurgical anastomosis
AC C
with the presence of a vertical interval. J Reconstr Microsurg. 2013 Mar;29(3):205-8 18. Maegawa J, Yabuki Y, Tomoeda H, Hosono M, Yasumura K. Outcomes of lymphaticovenous side-to-end anastomosis in peripheral lymphedema. J Vasc Surg. 2012 Mar;55(3):753-60.
19. 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.
Mar;125(3):935-43. 11
2010
ACCEPTED MANUSCRIPT
20. Koshima I, Kawada S, Moriguchi T, Kajiwara Y. Ultrastructural observations of lymphatic vessels in lymphedema in human extremities. Plast Reconstr Surg. 1996
AC C
EP
TE D
M AN U
SC
RI PT
Feb;97(2):397-405
12
ACCEPTED MANUSCRIPT
Figure Legends Figure 1: Left: In the proximal pattern, DBF appears in the proximal side of the limb and spreads to the distal and contralateral sides. Right: In the distal pattern, DBF
Backflow pattern.
RI PT
appears in the distal side of the limb and spreads to the proximal side. DBF: Dermal
Figure 2: Initial stage of the proximal pattern of secondary lower limb lymphedema: DBF appears in only the left inguinal region, and normal linear signs of lymphatics are
SC
seen in ICG lymphography and marked with dashed lines.
Figure 3: In the proximal pattern, DBF spreads from the proximal inguinal region to
M AN U
the distal and contralateral sides. DBF was appeared from left inguinal region to left ankle and right inguinal region in this patient. Dashed lines show linear lines of lymphatic channels appeared in ICG lymphography.
Figure 4: In the terminal stage of the proximal pattern, DBF spreads throughout the
TE D
limbs and the abdominal and genital regions.
Figure 5: In the proximal pattern, collateral lymphatics from abdominal region to ipsilateral axillar lymph nodes are sometimes identified in ICG lymphography because of its strong lymphatics pump function. DBF was appeared whole left lower limb, right
EP
thigh, abdominal and genital regions. Dashed lines show linear lines of lymphatic
AC C
channels appeared in ICG lymphography. Figure 6: In the distal pattern, DBF appears in the distal side of the limb and spreads to the proximal side. DBF was appeared from left foot to knee in this patient. In many cases, the contralateral side shows normal linear lymphatic pattern. Dashed lines show linear lines of lymphatic channels appeared in ICG lymphography. Figure 7: In the terminal stage of the distal pattern of secondary lower limb lymphedema, DBF stays only in the distal lower leg and severe edema appeared, whereas contralateral lower limb is almost normal. DBF was appeared from right foot
ACCEPTED MANUSCRIPT
to part of thigh in this patient. Dashed lines show linear lines of lymphatic channels
AC C
EP
TE D
M AN U
SC
RI PT
appeared in ICG lymphography.
ACCEPTED MANUSCRIPT
Table 1 Characteristics of patients.
No. of cases
90
No. of limbs
180
Sex Female
88
Male
2
No. of Bilateral lymphedema cases
46
No. of Unilateral cases
44
Etiology 46
Uterine Body Cancer
M AN U
Cervical Cancer
27
Ovarian Cancer
10
Others
6
Average Duration of Edema, yr
5.9
Average Duration of Compression therapy , yr Radiation therapy
4.5
37
History of Phlegmone Yes
EP
No
TE D
Yes No
53
65 25
AC C
ISL lymphedema stage
0
28
1
29
2
93
3
30
ICG location
proximal pattern
64
distal pattern
18
mixed pattern (proximal and distal pattern)
RI PT
59
SC
Average Age (range), yr
8
AC C
EP
TE D
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT
AC C
EP
TE D
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT
AC C
EP
TE D
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT
AC C
EP
TE D
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT
AC C
EP
TE D
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT
AC C
EP
TE D
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT
AC C
EP
TE D
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT
S1748-6815(15)00526-4
DOI:
10.1016/j.bjps.2015.10.042
Reference:
PRAS 4817
To appear in:
Journal of Plastic, Reconstructive & Aesthetic Surgery
Received Date: 18 August 2015 Revised Date:
23 October 2015
Accepted Date: 25 October 2015
Please cite this article as: Tashiro K, Yamashita S, Saito T, Iida T, Koshima I, Proximal and Distal Patterns: Different Spreading Patterns of Indocyanine Green Lymphography in Secondary Lower Extremity Lymphedema, British Journal of Plastic Surgery (2015), doi: 10.1016/j.bjps.2015.10.042. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
Title: Proximal and Distal Patterns: Different Spreading Patterns of Indocyanine Green
RI PT
Lymphography in Secondary Lower Extremity Lymphedema
Authors:
Kensuke Tashiro M.D., Shuji Yamashita M.D., Takafumi Saito M.D., Takuya Iida M.D.,
SC
Isao Koshima M.D.
Affiliation:
Tokyo, Japan
Corresponding Author: Kensuke Tashiro, M.D.
EP
Assistant professor
TE D
Financial Disclosure: None
M AN U
Department of Plastic and Reconstructive Surgery, University of Tokyo
Department of Plastic and Reconstructive Surgery, Graduate School of Medicine,
AC C
University of Tokyo, 7-3-1, Hongo, Bunkyo-ku Tokyo, Japan, 113-8655 Phone: 81-3-3815-5411 Fax: 81-3-5800-6929 E-mail: [email protected]
1
ACCEPTED MANUSCRIPT
Abstract [Background] As clinical evaluation of secondary lymphedema of the leg, indocyanine green (ICG)
RI PT
lymphographic assessment has been established its usefulness. In this study, we analyzed the ICG findings of patients with secondary lymphedema of the leg, focusing on the location and spreading pattern of dermal backflow (DBF).
SC
[Methods]
We investigated ICG findings of 90 patients with secondary lymphedema of the leg
M AN U
following malignant cancer resection between April 2013 and June 2015. The patients comprised 88 women and 2 men, and ICG lymphography was performed 12 to 24 hours after the injection.
TE D
[Results]
In 64 of the 90 patients, ICG lymphographic DBF was evident from the proximal region of the leg, and this type was termed the proximal pattern. In 18 of the 90 patients, DBF
AC C
pattern.
EP
appeared mainly in the distal part of the leg, and this type was termed the distal
[Conclusions]
In proximal pattern, the ICG injected into the distal part of the leg propelled to the proximal part of the leg, but an obstruction after lymphadenectomy caused ICG pooling to appear first on the proximal side. In distal pattern, hypoplasia of the lymphatic system of the leg may have already been present, and lymph node dissection might be only the trigger for the development of lymphedema. This classification may reflect the pumping function and preexisted hypoplasty of the lymphatic vessels, and provides a 2
ACCEPTED MANUSCRIPT
novel approach for the pathological evaluation of lymphedema. Patients of proximal pattern in ICG lymphography may be good indication for lymphatico-venous
AC C
EP
TE D
M AN U
SC
RI PT
anastomosis.
3
ACCEPTED MANUSCRIPT
Introduction Lymphedema occurs when lymph accumulates in the subcutaneous interstitium. The
RI PT
accumulation of protein-rich lymph causes inflammation, adipose tissue hypertrophy, and fibrosis, which not only causes cosmetic problems but also reduces mobility and function.1 As the condition becomes more severe, cellulitis often develops, which in the worst-case scenario can result in the development of fatal lymphangiosarcoma.
SC
Lymphedema is classified as primary or secondary depending on the cause: the former is believed to be due to lymphatic vessel hypoplasia, and the latter owing to obstruction
M AN U
of the central lymphatic system because of infection, cancer surgery, radiotherapy, or other causes.
Lymphedema is treated either surgically or conservatively. Surgery is carried out with the aim either of removing edematous tissue or of restoring lymphatic vessel function.
TE D
In the former case, fat resection or liposuction may be used, and in the latter, lymphaticovenous anastomosis (LVA) or lymph node transfer may be performed. 2,3,4 The methods commonly used to assess the severity of lymphedema include
EP
lymphoscintigraphy, magnetic resonance (MR) lymphography, and indocyanine green (ICG) lymphography. Lymphoscintigraphy has the advantage of providing wide-ranging
AC C
images of the entire leg, but is less useful for detailed evaluation. 5,6 MR lymphography similarly enables the assessment of the entire affected limb without the need for radiation exposure or drug administration, but does not allow lymphatic vessel function to be monitored in real time. 7 ICG lymphography enables the real-time assessment of lymphatic vessel function and can be used in lymphatic vessel surgery. It is minimally invasive, and accurately reflects the severity of lymphedema. 8,9,10 ICG lymphography has been used previously to assess the severity of lymphedema. 8,9,10 In secondary lymphedema of the leg following cancer surgery, dermal backflow (DBF) 4
ACCEPTED MANUSCRIPT
pattern occurs in the groin initially, and this descends to the thigh and lower leg; the DBF pattern may also change in tone to stardust or diffuse. In this study, we analyzed the ICG findings of patients with secondary lymphedema of the leg, and found that the
RI PT
findings can be broadly divided into two types according to the location of DBF. We describe these as proximal and distal patterns. This classification reflects the pumping function of the lymphatic vessels, and provides a novel approach for the pathological evaluation of lymphedema. It may also be useful as an index for predicting the
SC
effectiveness of LVA.
M AN U
Patients and Methods
We investigated ICG findings of 90 patients with secondary lymphedema of the leg following malignant cancer resection between April 2013 and June 2015. This study was approved by the Institutional Review Board of the University of Tokyo Hospital,
TE D
and was carried out retrospectively. Detailed patient information, including etiology, is listed in Table 1. The mean age was 59 years, and the mean duration of lymphedema was 4 years. The patients comprised 88 women and 2 men, with a mean body mass
EP
index (BMI) of 24.2. The underlying disease was cervical cancer in 46 cases, uterine cancer in 28, ovarian cancer in 10, and prostate cancer, penile cancer, colorectal cancer,
AC C
uterine sarcoma, Paget’s disease of the vulva, and malignant lymphoma in 1 case each. Radiotherapy was administered in 37 cases, and 65 patients had a history of cellulitis. In terms of the International Society of Lymphology (ISL) staging, 28 legs were Stage 0, 29 Stage 1, 93 Stage 2, and 30 Stage 3. ICG lymphography was performed as follows: 0.2 ml of ICG (Diagnogreen 0.25%; Daiichi Pharmaceutical, Tokyo, Japan) was injected subcutaneously into both lower extremities at the first web space of the foot and the lateral border of the Achilles tendon. Imaging was performed using a Photodynamic Eye (Hamamatsu Photonics, 5
ACCEPTED MANUSCRIPT
Hamamatsu, Japan) 12 to 24 hours after the injection. ICG lymphography images were recorded at a plateau phase of the lymphography. The diagnosis of ICG lymphographic patterns, proximal or distal patterns, were made by plastic surgeons trained for
RI PT
lymphedema treatment.
Results
A pattern of fluorescent contrast from the proximal region on ICG lymphography was
SC
evident in 64 of the 90 patients. This type was termed the proximal pattern. Cases in which DBF was evident in the entire leg were also classified as exhibiting the proximal
M AN U
pattern. When the proximal pattern was evident, the ICG injected into the distal part of the leg propelled to the proximal part of the leg, but an obstruction at a more central location caused ICG pooling to appear first on the proximal side. DBF that appeared first in the distal part of the leg on ICG lymphography was evident
TE D
in 18 of the 90 patients. This type was termed the distal pattern. In this pattern, the ICG injected into the distal part of the leg could not be propelled to the proximal region, meaning that ICG pooling only appeared in the distal region. Given the pathological
present.
EP
background, this suggested that lymphatic vessel hypoplasia already may have been
AC C
In 8 of the 90 patients, one leg exhibited the proximal pattern and the other the distal pattern on ICG lymphography. The leg that exhibited the proximal pattern, lymphatic vessel function was normal, and a central obstruction resulted in ICG pooling closer to the trunk, while the leg that exhibited the distal pattern, lymphatic vessel hypoplasia showed in ICG pooling at the distal end. Collateral lymphatic channels leading from lower abdomen to the axillary lymph nodes were present in 6 of the 64 patients who exhibited the proximal pattern. These represented the formation of lymph drainage channels as an attempt to drain the 6
ACCEPTED MANUSCRIPT
lymphatic fluid pooled in the lower abdomen and below, and reflected the vigorous pump function of the lymphatic vessels that produced the proximal pattern.
RI PT
Discussion We report a new classification of ICG lymphography findings for secondary lymphedema of the legs after cancer surgery. Yamamoto et al. previously have reported the use of ICG lymphography to assess the severity of secondary lymphedema of the
SC
legs after cancer surgery. 10 They found, that according to the progression of secondary lymphedema of the legs, the dermal backflow initially had a splash pattern in the groin,
M AN U
which gradually descended toward the foot until it extended throughout the entire leg. We analyzed ICG lymphography findings from 90 patients with secondary lymphedema of the legs, and showed that they could broadly be divided into two patterns: proximal and distal patterns.
TE D
In the proximal pattern, DBF initially appeared at the proximal end of the legs and gradually descended. In this pattern, ICG lymphography also frequently reveals DBF in the abdomen, and sometimes, in the genital region. It often exhibits a linear pattern of
EP
lymphatic ducts in the distal part of the leg, where lymphatic vessel function is usually normal. The pumping function of the lymphatic vessels is well maintained throughout
AC C
the leg, and ICG injected subcutaneously in the foot is propelled to the proximal part of the leg, but obstruction of the lymphatic vessels in the abdominal cavity causes lymphatic fluid to be retained in the abdomen or upper leg, resulting in the development of lymphedema. 11 In this proximal pattern, collateral lymphatic channel formation may occasionally be seen past the watershed of the umbilicus toward ipsilateral axillary lymph nodes. In this study, we observed collateral lymphatic vessels in 6 of 64 patients who exhibited the proximal pattern. These collateral lymphatic channels may have been formed because of 7
ACCEPTED MANUSCRIPT
the vigorous pumping function of the lymphatic vessels creating new drainage channels from lower abdomen to ipsilateral axillary lymph nodes. 12,13,14,15 In the distal pattern, DBF starts from the distal part of the leg. Fluorescence is not
RI PT
generally evident in the proximal part on ICG lymphography, indicating that the lymphatic system in the leg is not capable of propelling ICG upward. Hypoplasia of the lymphatic system of the leg may have already been present in such patients, and lymph node dissection was only the trigger for the development of lymphedema, with
SC
lymphatic system hypoplasia being the main cause. Underlying the distal pattern is thus latent lymphatic vessel hypoplasia, which is the main cause of primary
M AN U
lymphedema, and this is a different pathological mechanism compared to that involved in secondary lymphedema exhibiting the proximal pattern, which has a central obstruction of the lymphatic system as its basis.
Primary lymphedema is frequently triggered by mild trauma such as a sprain or
TE D
compression from a bandage. This tends to be more common from adolescence through to middle age. Although many aspects of the etiology of primary lymphedema remain unclear, lymphatic vessel hypoplasia is believed to be the underlying mechanism.
EP
Primary and secondary lymphedema exhibit different patterns on ICG lymphography. In light of our results in this study, some cases previously classified as secondary
AC C
lymphedema may actually be similar to primary lymphedema caused by lymphatic vessel hypoplasia.
The effectiveness of LVA is influenced by the condition of the lymphatic vessels. The stronger their pumping action, the greater the volume of lymphatic fluid that can be drained, causing improvement in lymphedema. Although LVA may greatly improve lymphedema with minimal invasiveness, there are no clear indication criteria, and it is ineffective in some cases.
16,17,18,19
Our results indicated that preoperative ICG
lymphography may enable the pumping function of the lymphatic vessels to be assessed, 8
ACCEPTED MANUSCRIPT
clarifying whether LVA is indicated. In patients who exhibit the proximal pattern, the underlying pumping function of the lymphatic vessels is well maintained, and LVA is more likely to be effective. In those who exhibit the distal pattern, however, the
RI PT
pumping function of the lymphatic vessels is already poor, and LVA may be relatively ineffective.
Our study indicated that the location of the appearance of DBF may be as important as its tone in ICG lymphography. This is because it provides an indication of the pumping
SC
ability of the lymphatic vessels, a function of smooth muscle.20 Our results also suggested that the condition of the lymphatic vessels may vary even within a single leg,
M AN U
indicating the diverse pathology of lymphedema. The use of ICG lymphography may clearly reveal the condition of the lymphatic vessels.
Conclusion
TE D
Secondary lymphedema can be classified into two types depending on the location of appearance of DBF on ICG lymphography. We categorize these as proximal and distal patterns. These may reflect the pumping function of the lymphatic vessels, and patients
EP
of proximal pattern in ICG lymphography may be good indication for LVA.
AC C
Funding: None declared.
Conflicts of Interest Statement: None declared.
References
1. Kerchner K, Fleischer A, Yosipovitch G. Lower extremity lymphedema update: pathophysiology, diagnosis, and treatment guidelines. J Am Acad Dermatol. 2008 Aug;59(2):324-31 2. Koshima I, Nanba Y, Tsutsui T, et al. Minimal invasive lymphaticovenular 9
ACCEPTED MANUSCRIPT
anastomosis under local anesthesia for leg lymphedema: is it effective for stage III and IV? Ann Plast Surg 2004; 53: 261-6. 3. Koshima I, Narushima M, Yamamoto Y, Mihara M, Iida T. Recent advancement on
RI PT
surgical treatments for lymphedema. Ann Vasc Dis. 2012;5(4):409-15. 4. Becker C, Assouad J, Riquet M, Hidden G. Postmastectomy lymphedema: long-term results following microsurgical lymph node transplantation. Ann Surg. 2006 Mar;243(3):313-5.
SC
5. Samuels LD. Lymphoscintigraphy. Lymphology. 1987 Mar;20(1):4-9.
6. Iimura T, Fukushima Y, Kumita S, Ogawa R, Hyakusoku H. Estimating Conditions
and
Lymphovenous
Anastomosis
M AN U
Lymphodynamic
Efficacy
Using
(99m)Tc-phytate Lymphoscintigraphy with SPECT-CT in Patients with Lower-limb Lymphedema. Plast Reconstr Surg Glob Open. 2015 Jun 5;3(5):e404. 7. Lu Q, Delproposto Z, Hu A, Tran C, Liu N, Li Y, Xu J, Bui D, Hu J. MR lymphography
TE D
of lymphatic vessels in lower extremity with gynecologic oncology-related lymphedema. PLoS One. 2012;7(11):e50319.
8. Ogata F, Azuma R, Kikuchi M, Koshima I, Morimoto Y. Novel lymphography using
EP
indocyanine green dye for near-infrared fluorescence labeling. Ann Plast Surg. 2007 Jun;58(6):652-5.
AC C
9. 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 Aug;59(2):180-4. 10. Yamamoto T, Narushima M, Doi K, Oshima A, Ogata F, Mihara M, Koshima I, Mundinger GS. 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 May;127(5):1979-86. 11. Gómez FM, Martínez-Rodrigo J, Martí-Bonmatí L, Santos E, Forner I, Lloret M, 10
ACCEPTED MANUSCRIPT
Pérez-Enguix D, García-Marcos R. Transnodal lymphangiography in the diagnosis and treatment of genital lymphedema. Cardiovasc Intervent Radiol. 2012 Dec;35(6):1488-91. 12. Sappey MPC (1874) Anatomie, physiologie, pathologie des vaisseaux lymphatiques
RI PT
consideres chez l’homme at les vertebres. Paris: A. Delahaye and E. Lecrosnier. 13. Suami H, Yamashita S, Soto-Miranda MA, Chang DW. Lymphatic territories (lymphosomes) in a canine: an animal model for investigation of postoperative lymphatic alterations. PLoS One. 2013 Jul 24;8(7):e69222.
SC
14. Bobbio P, Peracchia G, Pellegrino F (1962) Connessioni linfatiche presternali fra le regioni mammarie dei due lati. Ateneo Parmensa 33(supp.): 95–109.
M AN U
15. Tashiro K, Shibata T, Mito D, Ishiura R, Kato M, Yamashita S, Narushima M, Iida T, Koshima I. Indocyanine Green Lymphographic Signs of Lymphatic Collateral Formation in Lower Extremity Lymphedema after Cancer Resection. Annals of Plastic Surgery. In press.
TE D
16. Akita S, Mitsukawa N, Rikihisa N, Kubota Y, Omori N, Mitsuhashi A, Tate S, Shozu M, Satoh K. Early diagnosis and risk factors for lymphedema following lymph node dissection for gynecologic cancer. Plast Reconstr Surg. 2013 Feb;131(2):283-90.
EP
17. Tashiro K, Mihara M, Todokoro T, Narushima M, Yamamoto T, Iida T, Araki J, Iwamoto T, Koshima I. Christmas tree background for supermicrosurgical anastomosis
AC C
with the presence of a vertical interval. J Reconstr Microsurg. 2013 Mar;29(3):205-8 18. Maegawa J, Yabuki Y, Tomoeda H, Hosono M, Yasumura K. Outcomes of lymphaticovenous side-to-end anastomosis in peripheral lymphedema. J Vasc Surg. 2012 Mar;55(3):753-60.
19. 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.
Mar;125(3):935-43. 11
2010
ACCEPTED MANUSCRIPT
20. Koshima I, Kawada S, Moriguchi T, Kajiwara Y. Ultrastructural observations of lymphatic vessels in lymphedema in human extremities. Plast Reconstr Surg. 1996
AC C
EP
TE D
M AN U
SC
RI PT
Feb;97(2):397-405
12
ACCEPTED MANUSCRIPT
Figure Legends Figure 1: Left: In the proximal pattern, DBF appears in the proximal side of the limb and spreads to the distal and contralateral sides. Right: In the distal pattern, DBF
Backflow pattern.
RI PT
appears in the distal side of the limb and spreads to the proximal side. DBF: Dermal
Figure 2: Initial stage of the proximal pattern of secondary lower limb lymphedema: DBF appears in only the left inguinal region, and normal linear signs of lymphatics are
SC
seen in ICG lymphography and marked with dashed lines.
Figure 3: In the proximal pattern, DBF spreads from the proximal inguinal region to
M AN U
the distal and contralateral sides. DBF was appeared from left inguinal region to left ankle and right inguinal region in this patient. Dashed lines show linear lines of lymphatic channels appeared in ICG lymphography.
Figure 4: In the terminal stage of the proximal pattern, DBF spreads throughout the
TE D
limbs and the abdominal and genital regions.
Figure 5: In the proximal pattern, collateral lymphatics from abdominal region to ipsilateral axillar lymph nodes are sometimes identified in ICG lymphography because of its strong lymphatics pump function. DBF was appeared whole left lower limb, right
EP
thigh, abdominal and genital regions. Dashed lines show linear lines of lymphatic
AC C
channels appeared in ICG lymphography. Figure 6: In the distal pattern, DBF appears in the distal side of the limb and spreads to the proximal side. DBF was appeared from left foot to knee in this patient. In many cases, the contralateral side shows normal linear lymphatic pattern. Dashed lines show linear lines of lymphatic channels appeared in ICG lymphography. Figure 7: In the terminal stage of the distal pattern of secondary lower limb lymphedema, DBF stays only in the distal lower leg and severe edema appeared, whereas contralateral lower limb is almost normal. DBF was appeared from right foot
ACCEPTED MANUSCRIPT
to part of thigh in this patient. Dashed lines show linear lines of lymphatic channels
AC C
EP
TE D
M AN U
SC
RI PT
appeared in ICG lymphography.
ACCEPTED MANUSCRIPT
Table 1 Characteristics of patients.
No. of cases
90
No. of limbs
180
Sex Female
88
Male
2
No. of Bilateral lymphedema cases
46
No. of Unilateral cases
44
Etiology 46
Uterine Body Cancer
M AN U
Cervical Cancer
27
Ovarian Cancer
10
Others
6
Average Duration of Edema, yr
5.9
Average Duration of Compression therapy , yr Radiation therapy
4.5
37
History of Phlegmone Yes
EP
No
TE D
Yes No
53
65 25
AC C
ISL lymphedema stage
0
28
1
29
2
93
3
30
ICG location
proximal pattern
64
distal pattern
18
mixed pattern (proximal and distal pattern)
RI PT
59
SC
Average Age (range), yr
8
AC C
EP
TE D
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT
AC C
EP
TE D
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT
AC C
EP
TE D
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT
AC C
EP
TE D
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT
AC C
EP
TE D
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT
AC C
EP
TE D
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT
AC C
EP
TE D
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT