ORIGINAL ARTICLE
Vascularized Lymph Node Transfer for Treatment of Lymphedema A Comprehensive Literature Review Ashvin Raju, MD∗ and David W. Chang, MD† Objective: A comprehensive literature review of VLNT with updates and comparisons on current application, techniques, results, studies and possible future implications. Background: Lymphedema is a debilitating condition that often results secondary to treatment of cancer. Unfortunately there is no cure. However, microsurgical procedures such as VLNT has gained popularity as there have been increasing reports that VLNT may help alleviate the severity of lymphedema. Methods: A review of literature was conducted over major medical indices (PubMed-MEDLINE, Factiva, Scopus, Sciencedirect, EMBASE). Search terms were focused on vascularized, lymph node transfer (also autologous, lymph node transplant) to cover both human and animal studies. Each study was verified for the nature of the procedure; a free microsurgical flap containing lymph nodes for the purpose of relieving lymphedema. Results: There are human and animal studies that individually report clear benefits, but because of methodological shortcomings comparative studies with uniform patient selection and monitoring are lacking. Conclusions: Although the results with the use of VLNT for treatment of lymphedema have been largely positive, further exploration into standardized protocols for diagnosis, treatment optimization, and patient outcomes assessment is needed. Keywords: lymphedema, microsurgery, treatment of lymphedema, vascularized lymph node transfer (Ann Surg 2015;261:1013–1023)
S
econdary lymphedema has been reported to occur in up to 49% of breast cancer patients after mastectomy, and in up to 28% of patients who underwent lumpectomy.1 Factors such as obesity, extent of axillary surgery, radiotherapy, infection, and trauma have been identified to predispose to the condition.1,2 It is thought that lymphatic obstruction or destruction by surgery and radiation leads disturbance in lymphatic fluid transport that leads to significant rises in both subcutaneous and intramuscular compartment pressures.3 As lymphatics reabsorb remnant fluid in the interstitium, a progressive buildup of fluid ensue.4 Moreover, as macromolecules such as protein aggregate in the interstitial space, fluid is driven out from surrounding vessels, worsening the buildup.4 The condition is further compounded as both lymphatic and From the ∗ Yong Loo Lin School of Medicine, National University of Singapore, Singapore; and †Section of Plastic and Reconstructive Surgery, Department of Surgery, The University of Chicago Medicine and Biological Sciences, Chicago, IL. Disclosure: The authors declare there are no conflicts of interest. No funding was received in support of this work. Reprints: David W. Chang, MD, FACS, Section of Plastic and Reconstructive Surgery, Department of Surgery, The University of Chicago Medicine and Biological Sciences, 5841 S Maryland Ave, Rm J641, MC 6035, Chicago, IL 60637. E-mail: [email protected]. C 2014 Wolters Kluwer Health, Inc. All rights reserved. Copyright ISSN: 0003-4932/14/26105-1013 DOI: 10.1097/SLA.0000000000000763
Annals of Surgery r Volume 261, Number 5, May 2015
capillary flow becomes incrementally obstructed due to the increasing surrounding pressure of various tissue compartments.3 Histologically, proximal degeneration of lymphatics has been described to occur rapidly after lymphadenectomy due to excessive dilatation of related lymph channels.5 The powerful contractile mechanism of lymphatic smooth muscles, however, may not be restored and further exacerbated by repeated episodes of lymphangitic infection.5 It has also been found that lymphatic function in the peripheries is often intact in patients with lymphedema, but the vessels largely have lymph backflow with valve insufficiency.5 Conservative treatments to address this condition include compression techniques, manual lymphatic drainage, and mechanical measures such as intermittent pneumatic compression and laser therapy.6 Current research into conservative therapy has not shown a single most impactful method and that the long-term effects of these methods on the whole might not be clinically significant.6 Moreover, patient compliance can be affected adversely, which can negatively impact long-term outcome.4 However, complete decongestive therapy is generally considered to be the criterion standard modality in the management of lymphedema.2 Surgical therapies have been developed to tackle conservative treatment-resistant lymphedema. Excisional procedures have the benefit of vast improvement (size reduction of up to 118%), but also there are numerous complications which include destruction of remnant lymphatics, return of swelling, gross aesthetic deformity, and unstable scars.2 Lymphatic reconstructive procedures such as lymphovenous bypass have been shown to be useful especially in cases of mild lymphedema before development of fibrosis, but can be technically difficult due to the requirement of supermicrosurgical instruments for vessels less than 1 mm.1,7 Autologous or vascularized lymph node transfer (VLNT) was first pioneered successfully in an animal model by Shesol in 1979 and used clinically for a patient by Clodius et al in 1982.8,9 This procedure aims to bring vascularized tissue and healthy lymph nodes into sites affected by lymphedema. One theory is that lymphangiogenesis occur via growth factors produced by the transplanted lymph nodes and thereby bridge lymphatic pathways.1 Another theory proposed is that vascularized lymph node transfer acts as a lymphatic pump.3 VLNT will be the focus of this review article with updates and comparisons on current application, techniques, results, animal studies and possible future implications.
MATERIALS AND METHODS A review of English and non-English literature was conducted over major medical indices (PubMed-MEDLINE, Factiva, Scopus, Science direct, EMBASE). Search terms were focused on vascularized, lymph node transfer (also autologous, lymph node transplant) to cover both human and animal studies. Each study was verified for the nature of the procedure; a free microsurgical flap containing lymph nodes for the purpose of relieving lymphedema. A total of 22 studies, 12 in English literature and 10 in nonEnglish literature, were identified that fit the criteria. For the purpose www.annalsofsurgery.com | 1013
Copyright © 2014 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
Annals of Surgery r Volume 261, Number 5, May 2015
Raju and Chang
including animal studies (Table 1) is to identify new techniques, which can augment VLNT in the future, and to show the differences between various forms of lymph node transplant. Two pharmacologic measures have been identified, namely vascular endothelial growth factors (VEGF) and protein-rich plasma (PRP). Growth factor therapy seems to increase survival and function of transferred lymph nodes, whereas VEGF-C treated nodes result in retention of lymphatic structure, function as well as better collecting vessel formation and nodal histology compared to VEGF-D.11 Control lymph nodes regressed eventually and were replaced by adipose and fibrotic tissue.11 PRP is shown to improve survival rate of transplanted lymph nodes while causing B-cell proliferation, which might aid in infection control.12 The authors recommend a combination of surgical transplantation and synergistic growth factors in the treatment of lymphedema.11,12 Another study showed that VLNT specimens had lower edema measures and lymphatic function significantly greater (P < 0.0001) with a healthier appearance compared with avascular and control
of this article, only studies published in English literature, 7 human and 5 animal studies, were included. Because of the heterogeneity of study design, outcomes measures, and animal model type, the data were organized into table format for visual comparison. Additional animal studies were included to compare the results between vascularized versus avascularized nodal transfers.
RESULTS Our results of the literature search for up-to-date human and animal studies are summarized in Tables 1 to 4. Overall, VLNT results in both quantitative and qualitative improvements as seen in Tables 2 and 3. Animal studies (Table 1) show that whole nodal grafts and vascularized lymph node flaps both perform better than avascular cut lymph nodes, as well as the positive effects of growth factor therapy.
Animal Studies The capability of lymphatic regeneration is well known from various experimental models and flap transfers.10 The purpose of
TABLE 1. Animal Studies Author Tobbia et
al13
Chen et al47
Shesol et al9
Lahteenvuo et al11
Animal
Subjects
Type of Therapy
Follow-up, (wk)
Sheep
50
Surgery
12
Dog
10
Surgery
24
Rat
Pig
60
18
Surgery
Pharmacologic + Surgery
1
8
Parameters
Method
Results
Transport rate of HSA to Plasma (% injected/h) Decrease in mean excess circumference (%)
VLNT Avascular nodal graft Control VLNT
15.7 ± 1.0 12.6 ± 0.8 16.1 ± 0.7 Foot (7.8)
Evidence of radioactivity
No. vessels Increase in lymph flow vs control (%) No. vessels
Hadamitzky et al12
Blum et al14
Rat
Pig
44
26
1014 | www.annalsofsurgery.com
Pharmacologic + Surgery
Surgery
4
32
Increase in lymph flow vs control (%) No. vessels Proportion of regenerated lymph nodes (%)
Tc-99 m-NC-SPECT/CT
“ “ Lymphadenectomy Lymphadenectomy + lymph node island flap Lymphadenectomy + lymph node free flap Lymphadenectomy + lymph node graft Lymph node island flap VEGF C + VLNT “ VEGF D + VLNT “ Control + VLNT Whole avascular nodal graft Fragmented avascular nodal graft Fragmented avascular nodal graft + PRP Control Ipsilateral lymphadenectomy and avascular LNT Contralateral lymphadenectomy
Ankle (12.2) Midleg (10.5) 0/6 15/29 5/10 0/9 0/6 16.4 ± 2.8; P < 0.001 50 13.6 ± 3.6; P = 0.002 50 5.8 ± 1.6 80 50–65 100 0 No significant increase in diameter Impaired lymph flow and dermal backflow
C 2014 Wolters Kluwer Health, Inc. All rights reserved.
Copyright © 2014 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
Annals of Surgery r Volume 261, Number 5, May 2015
Vascularized Lymph Node Transfer for Treatment of Lymphedema
TABLE 2. Quantitative Human Studies Patients
Lymph Node Donor Site
Type of Flap
Recipient Site
Follow-up (mo)
7
Submental
VSLN
Ankle
8.7 (2–22)
Lin et al3
13
SCIV
Groin
Wrist
56 (6–96)
Saaristo et al10
9
SCIV
Groin
Axilla
6
Gharb et al17
21
Sb-SCIA
GroinStandard
Wrist
46 (26–120)
Groin-Hilar perforators
Wrist or forearm
40 (38–50)
Author Cheng et
al23
Becker et al15
24
SCIV
Groin
Axilla
60
Cheng et al21
8
Mbr-CF
Groin
Wrist
37 (12–54)
2
Mbr-CF
Groin
Elbow
33 (24–43)
Parameters
Reference Point
Results
Volume reduction Above knee rate (%) Below knee Above ankle Mean Arm circumference reduction rate (%) Mean Antebrachium circumference Brachium reduction rate (%) Mean Above elbow circumference Below elbow reduction rate Wrist (%) Palm Mean Above elbow circumference Below elbow reduction rate Wrist (%) Palm Circumference Return to normal change Unchanged >50% decrease
Vascularized Lymph Node Transfer for Treatment of Lymphedema A Comprehensive Literature Review Ashvin Raju, MD∗ and David W. Chang, MD† Objective: A comprehensive literature review of VLNT with updates and comparisons on current application, techniques, results, studies and possible future implications. Background: Lymphedema is a debilitating condition that often results secondary to treatment of cancer. Unfortunately there is no cure. However, microsurgical procedures such as VLNT has gained popularity as there have been increasing reports that VLNT may help alleviate the severity of lymphedema. Methods: A review of literature was conducted over major medical indices (PubMed-MEDLINE, Factiva, Scopus, Sciencedirect, EMBASE). Search terms were focused on vascularized, lymph node transfer (also autologous, lymph node transplant) to cover both human and animal studies. Each study was verified for the nature of the procedure; a free microsurgical flap containing lymph nodes for the purpose of relieving lymphedema. Results: There are human and animal studies that individually report clear benefits, but because of methodological shortcomings comparative studies with uniform patient selection and monitoring are lacking. Conclusions: Although the results with the use of VLNT for treatment of lymphedema have been largely positive, further exploration into standardized protocols for diagnosis, treatment optimization, and patient outcomes assessment is needed. Keywords: lymphedema, microsurgery, treatment of lymphedema, vascularized lymph node transfer (Ann Surg 2015;261:1013–1023)
S
econdary lymphedema has been reported to occur in up to 49% of breast cancer patients after mastectomy, and in up to 28% of patients who underwent lumpectomy.1 Factors such as obesity, extent of axillary surgery, radiotherapy, infection, and trauma have been identified to predispose to the condition.1,2 It is thought that lymphatic obstruction or destruction by surgery and radiation leads disturbance in lymphatic fluid transport that leads to significant rises in both subcutaneous and intramuscular compartment pressures.3 As lymphatics reabsorb remnant fluid in the interstitium, a progressive buildup of fluid ensue.4 Moreover, as macromolecules such as protein aggregate in the interstitial space, fluid is driven out from surrounding vessels, worsening the buildup.4 The condition is further compounded as both lymphatic and From the ∗ Yong Loo Lin School of Medicine, National University of Singapore, Singapore; and †Section of Plastic and Reconstructive Surgery, Department of Surgery, The University of Chicago Medicine and Biological Sciences, Chicago, IL. Disclosure: The authors declare there are no conflicts of interest. No funding was received in support of this work. Reprints: David W. Chang, MD, FACS, Section of Plastic and Reconstructive Surgery, Department of Surgery, The University of Chicago Medicine and Biological Sciences, 5841 S Maryland Ave, Rm J641, MC 6035, Chicago, IL 60637. E-mail: [email protected]. C 2014 Wolters Kluwer Health, Inc. All rights reserved. Copyright ISSN: 0003-4932/14/26105-1013 DOI: 10.1097/SLA.0000000000000763
Annals of Surgery r Volume 261, Number 5, May 2015
capillary flow becomes incrementally obstructed due to the increasing surrounding pressure of various tissue compartments.3 Histologically, proximal degeneration of lymphatics has been described to occur rapidly after lymphadenectomy due to excessive dilatation of related lymph channels.5 The powerful contractile mechanism of lymphatic smooth muscles, however, may not be restored and further exacerbated by repeated episodes of lymphangitic infection.5 It has also been found that lymphatic function in the peripheries is often intact in patients with lymphedema, but the vessels largely have lymph backflow with valve insufficiency.5 Conservative treatments to address this condition include compression techniques, manual lymphatic drainage, and mechanical measures such as intermittent pneumatic compression and laser therapy.6 Current research into conservative therapy has not shown a single most impactful method and that the long-term effects of these methods on the whole might not be clinically significant.6 Moreover, patient compliance can be affected adversely, which can negatively impact long-term outcome.4 However, complete decongestive therapy is generally considered to be the criterion standard modality in the management of lymphedema.2 Surgical therapies have been developed to tackle conservative treatment-resistant lymphedema. Excisional procedures have the benefit of vast improvement (size reduction of up to 118%), but also there are numerous complications which include destruction of remnant lymphatics, return of swelling, gross aesthetic deformity, and unstable scars.2 Lymphatic reconstructive procedures such as lymphovenous bypass have been shown to be useful especially in cases of mild lymphedema before development of fibrosis, but can be technically difficult due to the requirement of supermicrosurgical instruments for vessels less than 1 mm.1,7 Autologous or vascularized lymph node transfer (VLNT) was first pioneered successfully in an animal model by Shesol in 1979 and used clinically for a patient by Clodius et al in 1982.8,9 This procedure aims to bring vascularized tissue and healthy lymph nodes into sites affected by lymphedema. One theory is that lymphangiogenesis occur via growth factors produced by the transplanted lymph nodes and thereby bridge lymphatic pathways.1 Another theory proposed is that vascularized lymph node transfer acts as a lymphatic pump.3 VLNT will be the focus of this review article with updates and comparisons on current application, techniques, results, animal studies and possible future implications.
MATERIALS AND METHODS A review of English and non-English literature was conducted over major medical indices (PubMed-MEDLINE, Factiva, Scopus, Science direct, EMBASE). Search terms were focused on vascularized, lymph node transfer (also autologous, lymph node transplant) to cover both human and animal studies. Each study was verified for the nature of the procedure; a free microsurgical flap containing lymph nodes for the purpose of relieving lymphedema. A total of 22 studies, 12 in English literature and 10 in nonEnglish literature, were identified that fit the criteria. For the purpose www.annalsofsurgery.com | 1013
Copyright © 2014 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
Annals of Surgery r Volume 261, Number 5, May 2015
Raju and Chang
including animal studies (Table 1) is to identify new techniques, which can augment VLNT in the future, and to show the differences between various forms of lymph node transplant. Two pharmacologic measures have been identified, namely vascular endothelial growth factors (VEGF) and protein-rich plasma (PRP). Growth factor therapy seems to increase survival and function of transferred lymph nodes, whereas VEGF-C treated nodes result in retention of lymphatic structure, function as well as better collecting vessel formation and nodal histology compared to VEGF-D.11 Control lymph nodes regressed eventually and were replaced by adipose and fibrotic tissue.11 PRP is shown to improve survival rate of transplanted lymph nodes while causing B-cell proliferation, which might aid in infection control.12 The authors recommend a combination of surgical transplantation and synergistic growth factors in the treatment of lymphedema.11,12 Another study showed that VLNT specimens had lower edema measures and lymphatic function significantly greater (P < 0.0001) with a healthier appearance compared with avascular and control
of this article, only studies published in English literature, 7 human and 5 animal studies, were included. Because of the heterogeneity of study design, outcomes measures, and animal model type, the data were organized into table format for visual comparison. Additional animal studies were included to compare the results between vascularized versus avascularized nodal transfers.
RESULTS Our results of the literature search for up-to-date human and animal studies are summarized in Tables 1 to 4. Overall, VLNT results in both quantitative and qualitative improvements as seen in Tables 2 and 3. Animal studies (Table 1) show that whole nodal grafts and vascularized lymph node flaps both perform better than avascular cut lymph nodes, as well as the positive effects of growth factor therapy.
Animal Studies The capability of lymphatic regeneration is well known from various experimental models and flap transfers.10 The purpose of
TABLE 1. Animal Studies Author Tobbia et
al13
Chen et al47
Shesol et al9
Lahteenvuo et al11
Animal
Subjects
Type of Therapy
Follow-up, (wk)
Sheep
50
Surgery
12
Dog
10
Surgery
24
Rat
Pig
60
18
Surgery
Pharmacologic + Surgery
1
8
Parameters
Method
Results
Transport rate of HSA to Plasma (% injected/h) Decrease in mean excess circumference (%)
VLNT Avascular nodal graft Control VLNT
15.7 ± 1.0 12.6 ± 0.8 16.1 ± 0.7 Foot (7.8)
Evidence of radioactivity
No. vessels Increase in lymph flow vs control (%) No. vessels
Hadamitzky et al12
Blum et al14
Rat
Pig
44
26
1014 | www.annalsofsurgery.com
Pharmacologic + Surgery
Surgery
4
32
Increase in lymph flow vs control (%) No. vessels Proportion of regenerated lymph nodes (%)
Tc-99 m-NC-SPECT/CT
“ “ Lymphadenectomy Lymphadenectomy + lymph node island flap Lymphadenectomy + lymph node free flap Lymphadenectomy + lymph node graft Lymph node island flap VEGF C + VLNT “ VEGF D + VLNT “ Control + VLNT Whole avascular nodal graft Fragmented avascular nodal graft Fragmented avascular nodal graft + PRP Control Ipsilateral lymphadenectomy and avascular LNT Contralateral lymphadenectomy
Ankle (12.2) Midleg (10.5) 0/6 15/29 5/10 0/9 0/6 16.4 ± 2.8; P < 0.001 50 13.6 ± 3.6; P = 0.002 50 5.8 ± 1.6 80 50–65 100 0 No significant increase in diameter Impaired lymph flow and dermal backflow
C 2014 Wolters Kluwer Health, Inc. All rights reserved.
Copyright © 2014 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
Annals of Surgery r Volume 261, Number 5, May 2015
Vascularized Lymph Node Transfer for Treatment of Lymphedema
TABLE 2. Quantitative Human Studies Patients
Lymph Node Donor Site
Type of Flap
Recipient Site
Follow-up (mo)
7
Submental
VSLN
Ankle
8.7 (2–22)
Lin et al3
13
SCIV
Groin
Wrist
56 (6–96)
Saaristo et al10
9
SCIV
Groin
Axilla
6
Gharb et al17
21
Sb-SCIA
GroinStandard
Wrist
46 (26–120)
Groin-Hilar perforators
Wrist or forearm
40 (38–50)
Author Cheng et
al23
Becker et al15
24
SCIV
Groin
Axilla
60
Cheng et al21
8
Mbr-CF
Groin
Wrist
37 (12–54)
2
Mbr-CF
Groin
Elbow
33 (24–43)
Parameters
Reference Point
Results
Volume reduction Above knee rate (%) Below knee Above ankle Mean Arm circumference reduction rate (%) Mean Antebrachium circumference Brachium reduction rate (%) Mean Above elbow circumference Below elbow reduction rate Wrist (%) Palm Mean Above elbow circumference Below elbow reduction rate Wrist (%) Palm Circumference Return to normal change Unchanged >50% decrease
