Special Topic Overview of Lymph Node Transfer for Lymphedema Treatment Ran Ito, M.D., Ph.D. Hiroo Suami, M.D., Ph.D. Houston, Texas
cpt
Summary: Recent articles report that surgery can effectively treat secondary lymphedema. Lymphovenous anastomosis with supermicrosurgery technique has become popular for surgical intervention for lymphedema and has an advantage of minimal morbidity. Lymphovenous anastomosis is effective for treating early-stage lymphedema before fibrosis occurs but has limited outcomes in advanced lymphedema. Lymph node transfer is an emerging physiologic surgical treatment for lymphedema that shows promise. The mechanisms of lymph node transfer have been discordant between publications. However, initial reports encourage surgeons to use lymph node transfer to treat lymphedema patients. The authors review the literature on lymph node transfer and discuss its possible mechanisms and its role in lymphedema treatment. (Plast. Reconstr. Surg. 134: 548, 2014.)
L
ymphedema is a chronic, progressive disease caused by the accumulation of extra fluid and protein deposits in the interstitial space, most frequently in the limbs. Lymph stasis induces an inflammatory reaction that leads to the proliferation of adipose tissue and to fibrosis, resulting in permanent, mild to severe swelling of the affected body parts.1 Lymphedema impairs quality of life through an increase in skin turgor, loss of dexterity, heaviness in the affected limbs, discomfort, pain, and recurrent infections.2 The standard treatment of lymphedema is called decongestive treatment, which consists of exercise, wearing a compression garment, skin care, and manual lymph drainage; however, surgery is sometimes needed in resistant and/or severe cases. Ablative operations and physiologic operations have been advocated for lymphedema treatment. Debulking surgery, an ablative operation, may be the simplest approach to reducing the volume of lymphedematous limbs but often causes substantial morbidity, including extensive scarring.3–5 For nonpitting lymphedema, liposuction can remove adipose tissue in the subcutaneous region,6 and the reduced limb volume can be maintained with continuous wearing of a compression garment.7 Lymphovenous anastomosis with supermicrosurgery technique, a mainstay From the Department of Plastic Surgery, The University of Texas M. D. Anderson Cancer Center. Received for publication November 26, 2013; accepted February 24, 2014. Copyright © 2014 by the American Society of Plastic Surgeons DOI: 10.1097/PRS.0000000000000383
548
among the physiologic surgical interventions for lymphedema, creates a detour route from the lymphatics to the vein at the peripheral region of the affected limb.8–15 Lymphovenous anastomosis has minimal morbidity and reportedly can be performed with local anesthesia.12–14 Several studies found that lymphovenous anastomosis was effective in early-stage lymphedema but less effective in advanced-stage lymphedema,9,13,16 possibly because the lymphatic vessels lose their ability to transfer lymph fluid in advanced lymphedema and because most of the patent lymphatic vessels suitable for lymphovenous anastomosis are deteriorated and difficult to find among the fibrotic tissues in severely lymphedematous limbs. Vascularized lymph node transfer is a relatively new physiologic surgical treatment for lymphedema. In vascularized lymph node transfer, vascularized lymph nodes are transferred into regions where lymph nodes have been dissected for cancer treatment or into distal regions of lymphedematous limbs to restore lymphatic drainage function. An early clinical report by Becker et al. showed promising outcomes.17 However, more evidence is needed to provide a rationale for using vascularized lymph node transfer. This article reviews the literature regarding lymph node transfer, with a focus on vascularized Disclosure: Neither of the authors has any source of financial or other support or any financial or professional relationships that might pose a competing interest.
www.PRSJournal.com
Volume 134, Number 3 • Lymph Node Transfer for Lymphedema lymph node transfer, and discusses its potential for the treatment of lymphedema. We summarize lymph node transfer in experimental and clinical settings, including its effects on limb and lymph flow improvement.
AVASCULARIZED LYMPH NODE TRANSFER IN ANIMAL STUDIES In 1928, Jaffe and Richter described lymph node transplantation using guinea pigs and albino rats.18 They harvested a cervical node and embedded it in the subcutaneous abdominal pocket. The experiments were unsuccessful in guinea pigs, with pyogenic infection, but transplanted lymph nodes maintained their normal gross appearance in over 90 percent of the albino rats. However, central necrosis of the transplanted lymph nodes was consistently observed in the rats studied in the early postoperative period.18 Tilak and Howard stressed the importance of preserving the continuity of afferent and efferent lymphatic pathways in lymph node restoration.19 They enucleated the medulla from the popliteal node in canines and transplanted fragments of lymph node medulla, which were harvested from the contralateral popliteal node, inside the capsule of the enucleated popliteal node.19 Grafting the medulla from the contralateral node to the capsule of the ipsilateral leg restored lymph node structures on lymphangiography, but grafting only sliced lymph nodes in the other group did not. In contrast, Blum et al. transplanted autologous lymph node fragments from the groin to ipsilateral groin or both groins in minipigs after lymphadenectomy and then demonstrated recanalization of the lymphatic system between afferent lymphatic vessels in the recipient limb and the transplanted lymph node fragments using dye injection and single-photon emission computed tomography.20,21 In an established lymphedema model in a rabbit ear, the skin, soft tissue, and perichondrium at the roof if the ear were excised circumferentially.22,23 Fu et al. then modified these models to create a vascular pedicle with rolled skin from the ventral side of the ear.24 Thin lymph node fragments were then transplanted into the auricular lymph node from the contralateral ear to the root of the ipsilateral ear to bridge the surgical gap between the lymphatic vessels. The transplanted lymph node fragments facilitated regeneration of the lymphatic tissue and contributed to reducing the volume of the lymphedematous rabbit ear.24 Avascularized lymph node transfer led to complete survival of the transplanted whole lymph
nodes in only a few of these animals. Subsequently, lymph nodes were cut into fragments and transplanted.19–27 How these fragments contributed to lymphatic regeneration is not well understood.
VASCULARIZED LYMPH NODE TRANSFER IN ANIMAL STUDIES In the 1970s, free tissue transfer with vascular anastomosis became a promising operative technique in which autologous tissue was harvested from a distant donor site and transferred to the target area. In 1979, a half-century after the report of avascularized lymph node transfer by Jaffe and Richter,18 Shesol et al. performed vascularized lymph node transfer in rats and found that vascularized lymph nodes survived completely with preservation of their original histologic structures.28 The study showed the importance of having a reliable blood supply to the lymph nodes to retain their structure and proved successful transfer of the nodes to the target area using microsurgical techniques.28,29 Chen et al. used a canine below-knee lymphedema model to perform vascularized lymph node transfer of the inguinal nodes to the lower hind limb.30 The transferred lymph nodes maintained their normal architecture 3 and 6 months after surgery.30 The lymphedematous limb circumferences were reduced after transplantation compared with their preoperative girth but never returned to their normal size. Postoperative lymphangiography demonstrated spontaneous recanalization of the lymphatic channels. Postoperative lymphoscintigraphy demonstrated uptake of a radiotracer by the transferred lymph node and liver, which had not been demonstrated in the preoperative lymphedematous limb. This result proved continuity from the foot to the systemic venous circulation by means of the vascularized lymph node transfer. Tobbia et al. compared lymphatic function after vascularized lymph node transfer and after avascularized lymph node transfer by assessing the transport rates of a protein tracer in a sheep model.31 They found that lymphatic function after vascularized lymph node transfer was not as good as that of the intact limbs but was better than that observed after avascularized lymph node transfer.31 Jeltsch et al. are credited with isolating vascular endothelial growth factor C (VEGF-C) and its receptor (VEGFR-3), which regulate lymphangiogenesis.32 Recent experimental studies combined VEGF-C administration with vascularized lymph
549
550
Circumference, lymphoscintigraphy
11
Circumference
7 (lower limb) 10 Circumference
14 (upper limb) Circumference, volumetry
9
36
Recipient Site (Recipient Vessels) Complications
Supraclavicular fossa (TCA, EJV, and TCV, or SCV)
Axilla (N/A) Groin (SCIA/V or SIEA/V)
Groin (N/A)
Foot (DPA/V)
None
Groin (N/A) Wrist (n = 8), Forearm cellulitis forearm (n = 2) (n = 1) (RA/V)
Axilla (N/A)
Cosmetic deepithelialization flap (4)
Wedge excision or suction-assisted liposuction (n = 2) None
Second VLNT inguinal to elbow (n = 7), physiotherapy (n = 9) Conservative therapy (stage 3)
Supplemental Treatment
Debulking surgery (n = 1), suctionassisted liposuction (n = 2) None
Compression and physiotherapy (n = 6) Lymphedema of Physiotherapy or donor (n = 4), compression (n = 21), donor-site pain suction-assisted (n = 4), lymphocele liposuction (n = 3) (n = 4), testicular hydrocele (n = 1)
Groin (SCIA/V Axilla (TDA/V), Repeated or SIEA/V), groin (SCIA/V) infection (2%) thoracic (TDA/V or LTA/V), supraclavicular fossa (TCA and EJV) Groin (SCIA/V) Wrist Wound infection (RA and CV) (n = 1), venous congestion (n = 1) Submentum Ankle (DPA/V) None (SMA/V) Groin (SCIA) Wrist (n = 8) None (RA and CV), elbow (n = 2) (UA and BV) Groin (SCIA/V Axilla (TDA/V) Delayed wound and IEA/V) closure (n = 2)
Follow-Up Donor Site (mo) (Donor Vessels)
SCIA/V, superficial circumflex iliac artery/vein; SIEA/V, superficial inferior epigastric artery/vein; TCA/V, transverse cervical artery/vein; SCV, superficial cervical vein; EJV, external jugular vein; TDA/V, thoracodorsal artery/vein; LTA/V, lateral thoracic artery/vein; RA/V, radial artery/vein; CV, cephalic vein; UA, ulnar artery; BV, basilic vein; SMA/V, submental artery/vein; DPA/V, dorsalis pedis artery/vein; N/A, not applicable. * The reduction rate of the circumference of the lymphedematous limb is [(a − b) − (c − d)]/(a −b), where a is the circumference of the preoperative affected limb, b is that of the preoperative healthy limb, c is that of the postoperative affected limb, and d is that of the postoperative healthy limb.
Sapountzis et al., 201345
Gharb et al., 201144
Vignes et al., 201343
Saaristo et al, 201239
Circumference, lymphoscintigraphy Circumference
7
Cheng et al., 201241 Cheng et al., 201342
10
Circumference, 50.55 ± 19.3 lymphoscintigraphy
13
Lin et al., 200938 64.9 ± 23.3
Circumference, 100 (900), lymphoscintigraphy,
cpt
Summary: Recent articles report that surgery can effectively treat secondary lymphedema. Lymphovenous anastomosis with supermicrosurgery technique has become popular for surgical intervention for lymphedema and has an advantage of minimal morbidity. Lymphovenous anastomosis is effective for treating early-stage lymphedema before fibrosis occurs but has limited outcomes in advanced lymphedema. Lymph node transfer is an emerging physiologic surgical treatment for lymphedema that shows promise. The mechanisms of lymph node transfer have been discordant between publications. However, initial reports encourage surgeons to use lymph node transfer to treat lymphedema patients. The authors review the literature on lymph node transfer and discuss its possible mechanisms and its role in lymphedema treatment. (Plast. Reconstr. Surg. 134: 548, 2014.)
L
ymphedema is a chronic, progressive disease caused by the accumulation of extra fluid and protein deposits in the interstitial space, most frequently in the limbs. Lymph stasis induces an inflammatory reaction that leads to the proliferation of adipose tissue and to fibrosis, resulting in permanent, mild to severe swelling of the affected body parts.1 Lymphedema impairs quality of life through an increase in skin turgor, loss of dexterity, heaviness in the affected limbs, discomfort, pain, and recurrent infections.2 The standard treatment of lymphedema is called decongestive treatment, which consists of exercise, wearing a compression garment, skin care, and manual lymph drainage; however, surgery is sometimes needed in resistant and/or severe cases. Ablative operations and physiologic operations have been advocated for lymphedema treatment. Debulking surgery, an ablative operation, may be the simplest approach to reducing the volume of lymphedematous limbs but often causes substantial morbidity, including extensive scarring.3–5 For nonpitting lymphedema, liposuction can remove adipose tissue in the subcutaneous region,6 and the reduced limb volume can be maintained with continuous wearing of a compression garment.7 Lymphovenous anastomosis with supermicrosurgery technique, a mainstay From the Department of Plastic Surgery, The University of Texas M. D. Anderson Cancer Center. Received for publication November 26, 2013; accepted February 24, 2014. Copyright © 2014 by the American Society of Plastic Surgeons DOI: 10.1097/PRS.0000000000000383
548
among the physiologic surgical interventions for lymphedema, creates a detour route from the lymphatics to the vein at the peripheral region of the affected limb.8–15 Lymphovenous anastomosis has minimal morbidity and reportedly can be performed with local anesthesia.12–14 Several studies found that lymphovenous anastomosis was effective in early-stage lymphedema but less effective in advanced-stage lymphedema,9,13,16 possibly because the lymphatic vessels lose their ability to transfer lymph fluid in advanced lymphedema and because most of the patent lymphatic vessels suitable for lymphovenous anastomosis are deteriorated and difficult to find among the fibrotic tissues in severely lymphedematous limbs. Vascularized lymph node transfer is a relatively new physiologic surgical treatment for lymphedema. In vascularized lymph node transfer, vascularized lymph nodes are transferred into regions where lymph nodes have been dissected for cancer treatment or into distal regions of lymphedematous limbs to restore lymphatic drainage function. An early clinical report by Becker et al. showed promising outcomes.17 However, more evidence is needed to provide a rationale for using vascularized lymph node transfer. This article reviews the literature regarding lymph node transfer, with a focus on vascularized Disclosure: Neither of the authors has any source of financial or other support or any financial or professional relationships that might pose a competing interest.
www.PRSJournal.com
Volume 134, Number 3 • Lymph Node Transfer for Lymphedema lymph node transfer, and discusses its potential for the treatment of lymphedema. We summarize lymph node transfer in experimental and clinical settings, including its effects on limb and lymph flow improvement.
AVASCULARIZED LYMPH NODE TRANSFER IN ANIMAL STUDIES In 1928, Jaffe and Richter described lymph node transplantation using guinea pigs and albino rats.18 They harvested a cervical node and embedded it in the subcutaneous abdominal pocket. The experiments were unsuccessful in guinea pigs, with pyogenic infection, but transplanted lymph nodes maintained their normal gross appearance in over 90 percent of the albino rats. However, central necrosis of the transplanted lymph nodes was consistently observed in the rats studied in the early postoperative period.18 Tilak and Howard stressed the importance of preserving the continuity of afferent and efferent lymphatic pathways in lymph node restoration.19 They enucleated the medulla from the popliteal node in canines and transplanted fragments of lymph node medulla, which were harvested from the contralateral popliteal node, inside the capsule of the enucleated popliteal node.19 Grafting the medulla from the contralateral node to the capsule of the ipsilateral leg restored lymph node structures on lymphangiography, but grafting only sliced lymph nodes in the other group did not. In contrast, Blum et al. transplanted autologous lymph node fragments from the groin to ipsilateral groin or both groins in minipigs after lymphadenectomy and then demonstrated recanalization of the lymphatic system between afferent lymphatic vessels in the recipient limb and the transplanted lymph node fragments using dye injection and single-photon emission computed tomography.20,21 In an established lymphedema model in a rabbit ear, the skin, soft tissue, and perichondrium at the roof if the ear were excised circumferentially.22,23 Fu et al. then modified these models to create a vascular pedicle with rolled skin from the ventral side of the ear.24 Thin lymph node fragments were then transplanted into the auricular lymph node from the contralateral ear to the root of the ipsilateral ear to bridge the surgical gap between the lymphatic vessels. The transplanted lymph node fragments facilitated regeneration of the lymphatic tissue and contributed to reducing the volume of the lymphedematous rabbit ear.24 Avascularized lymph node transfer led to complete survival of the transplanted whole lymph
nodes in only a few of these animals. Subsequently, lymph nodes were cut into fragments and transplanted.19–27 How these fragments contributed to lymphatic regeneration is not well understood.
VASCULARIZED LYMPH NODE TRANSFER IN ANIMAL STUDIES In the 1970s, free tissue transfer with vascular anastomosis became a promising operative technique in which autologous tissue was harvested from a distant donor site and transferred to the target area. In 1979, a half-century after the report of avascularized lymph node transfer by Jaffe and Richter,18 Shesol et al. performed vascularized lymph node transfer in rats and found that vascularized lymph nodes survived completely with preservation of their original histologic structures.28 The study showed the importance of having a reliable blood supply to the lymph nodes to retain their structure and proved successful transfer of the nodes to the target area using microsurgical techniques.28,29 Chen et al. used a canine below-knee lymphedema model to perform vascularized lymph node transfer of the inguinal nodes to the lower hind limb.30 The transferred lymph nodes maintained their normal architecture 3 and 6 months after surgery.30 The lymphedematous limb circumferences were reduced after transplantation compared with their preoperative girth but never returned to their normal size. Postoperative lymphangiography demonstrated spontaneous recanalization of the lymphatic channels. Postoperative lymphoscintigraphy demonstrated uptake of a radiotracer by the transferred lymph node and liver, which had not been demonstrated in the preoperative lymphedematous limb. This result proved continuity from the foot to the systemic venous circulation by means of the vascularized lymph node transfer. Tobbia et al. compared lymphatic function after vascularized lymph node transfer and after avascularized lymph node transfer by assessing the transport rates of a protein tracer in a sheep model.31 They found that lymphatic function after vascularized lymph node transfer was not as good as that of the intact limbs but was better than that observed after avascularized lymph node transfer.31 Jeltsch et al. are credited with isolating vascular endothelial growth factor C (VEGF-C) and its receptor (VEGFR-3), which regulate lymphangiogenesis.32 Recent experimental studies combined VEGF-C administration with vascularized lymph
549
550
Circumference, lymphoscintigraphy
11
Circumference
7 (lower limb) 10 Circumference
14 (upper limb) Circumference, volumetry
9
36
Recipient Site (Recipient Vessels) Complications
Supraclavicular fossa (TCA, EJV, and TCV, or SCV)
Axilla (N/A) Groin (SCIA/V or SIEA/V)
Groin (N/A)
Foot (DPA/V)
None
Groin (N/A) Wrist (n = 8), Forearm cellulitis forearm (n = 2) (n = 1) (RA/V)
Axilla (N/A)
Cosmetic deepithelialization flap (4)
Wedge excision or suction-assisted liposuction (n = 2) None
Second VLNT inguinal to elbow (n = 7), physiotherapy (n = 9) Conservative therapy (stage 3)
Supplemental Treatment
Debulking surgery (n = 1), suctionassisted liposuction (n = 2) None
Compression and physiotherapy (n = 6) Lymphedema of Physiotherapy or donor (n = 4), compression (n = 21), donor-site pain suction-assisted (n = 4), lymphocele liposuction (n = 3) (n = 4), testicular hydrocele (n = 1)
Groin (SCIA/V Axilla (TDA/V), Repeated or SIEA/V), groin (SCIA/V) infection (2%) thoracic (TDA/V or LTA/V), supraclavicular fossa (TCA and EJV) Groin (SCIA/V) Wrist Wound infection (RA and CV) (n = 1), venous congestion (n = 1) Submentum Ankle (DPA/V) None (SMA/V) Groin (SCIA) Wrist (n = 8) None (RA and CV), elbow (n = 2) (UA and BV) Groin (SCIA/V Axilla (TDA/V) Delayed wound and IEA/V) closure (n = 2)
Follow-Up Donor Site (mo) (Donor Vessels)
SCIA/V, superficial circumflex iliac artery/vein; SIEA/V, superficial inferior epigastric artery/vein; TCA/V, transverse cervical artery/vein; SCV, superficial cervical vein; EJV, external jugular vein; TDA/V, thoracodorsal artery/vein; LTA/V, lateral thoracic artery/vein; RA/V, radial artery/vein; CV, cephalic vein; UA, ulnar artery; BV, basilic vein; SMA/V, submental artery/vein; DPA/V, dorsalis pedis artery/vein; N/A, not applicable. * The reduction rate of the circumference of the lymphedematous limb is [(a − b) − (c − d)]/(a −b), where a is the circumference of the preoperative affected limb, b is that of the preoperative healthy limb, c is that of the postoperative affected limb, and d is that of the postoperative healthy limb.
Sapountzis et al., 201345
Gharb et al., 201144
Vignes et al., 201343
Saaristo et al, 201239
Circumference, lymphoscintigraphy Circumference
7
Cheng et al., 201241 Cheng et al., 201342
10
Circumference, 50.55 ± 19.3 lymphoscintigraphy
13
Lin et al., 200938 64.9 ± 23.3
Circumference, 100 (900), lymphoscintigraphy,
