RECONSTRUCTIVE Vascularized Lymph Node Transfer: A Review of the Current Evidence Saam S. Tourani, M.D. G. Ian Taylor, M.D. Mark W. Ashton, M.D. Parkville, Victoria, Australia
Summary: Over the past decade, lymph node transfer has rapidly gained popularity among plastic surgeons for the treatment of chronic lymphedema because of the initial promising results and its unique technical advantages compared with the other reconstructive options. However, its functional mechanism is still a matter of great debate, and some concerning reports have emerged regarding the safety of this procedure in patients with chronic lymphedema. The authors review the literature on the experimental and clinical evidence for lymph node transfer, discuss its proposed functional mechanisms, review the potential risk of iatrogenic lymphedema following this procedure, and discuss the suggested strategies to avoid this complication. (Plast. Reconstr. Surg. 137: 985, 2016.)
L
ymphedema is a chronic progressive condition in which accumulation of high-protein fluid in the interstitium induces cellular proliferation and inflammation that results in thickening and fibrosis of lymphatic vessels and surrounding tissue.1 Currently, there is no cure for this condition. The standard treatment is complete decongestive therapy that aims to improve the physical characteristics of the limb, alleviate symptoms, and reduce disease progression and secondary complications. Although effective in many patients, complete decongestive therapy is time consuming, difficult to perform on regular basis, and expensive.2 These barriers, together with a shortage of trained lymphedema therapists, lead to high rates of noncompliance and patient dissatisfaction. Surgical procedures for lymphedema are generally considered in two categories. Reductive methods such as direct excision or liposuction aim to remove the fibrofatty tissue that has been generated as a consequence of sustained lymph stasis. In contrast, physiologic (reconstructive) methods such as vascularized lymph node transfer and lymphovenous anastomosis aim to improve/restore the lymphatic drainage of the affected limb. In vascularized lymph node transfer, lymph nodes are harvested from a donor site and transferred as a free flap to the lymphedematous limb. Currently, two main hypotheses are postulated to From the Department of Anatomy and Neuroscience, University of Melbourne. Received for publication May 24, 2015; accepted October 26, 2015. Copyright © 2016 by the American Society of Plastic Surgeons DOI: 10.1097/01.prs.0000475827.94283.56
explain the functional mechanism of this procedure (i.e., the lymphatic wick and the lymphatic pump theory), with arguable experimental evidence available to support either one. Nevertheless, it has rapidly gained popularity among plastic surgeons since Becker et al. reported the first clinical series nearly a decade ago.3 This growing enthusiasm can perhaps be explained by both the initial promising results and some favorable technical factors associated with this procedure: 1. It is technically less challenging than lymphovenous anastomosis, as no lymphatic anastomosis is required. 2. It can be performed in more advanced cases of lymphedema where no suitable lymphatics can be found for lymphovenous anastomosis. 3. It can be performed in continuity with the deep inferior epigastric artery perforator flap for breast reconstruction. In this article, we first review the experimental evidence behind lymph node transfer. Second, the proposed functional mechanisms of vascularized lymph node transfer are discussed in view of the available evidence. Third, a brief summary of the published clinical series is given followed by a critical appraisal of their methodology. Fourth, the potential risk of iatrogenic lymphedema following this procedure and the suggested measures to avoid this complication are reviewed. Disclosure: The authors have no financial interest to declare in relation to the content of this article.
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Plastic and Reconstructive Surgery • March 2016 EXPERIMENTAL STUDIES Table 14–17 provides a summary of experimental studies on lymph node transfer. The earliest experiment is often credited to Jaffe and Richter in 1928.4 Although their experiment on stock guinea pigs failed because of infection, planting of intact cervical lymph nodes into the abdominal wall muscle of albino rats led to 90 percent take with complete regeneration of nodal architecture by day 6. Didukh reported 70 percent take following subcutaneous implantation of the intact lymph nodes in mice.5 Pabst and Rothkötter showed that transplanted lymph node fragments into the groin of minipigs not only regenerated into lymph node-like structures but also were integrated into the lymphatic drainage of the hind limb.6 In a similar experiment, Blum et al. used single-photon emission computed tomographic imaging to successfully demonstrate reintegration of lymph node fragments into the groin lymphatic drainage of minipigs.7 The above results generated hope for successfully using avascular autologous lymph node transplant to treat lymphedema. Fu et al. transferred lymph node fragments to an established lymphedema model in rabbit ears.8 Indirect lymphangiography 5 months postoperatively showed improved lymphatic drainage in the transplant group, with no dermal backflow. Although volume measurements showed significantly more volume reduction in the transplant group, the normal volumes were not achieved. In contrast, Tilak and Howard emphasized the importance of lymph node dual vascular supply on its viability.18 In their experiments on dogs,
lymph node fragments grafted into the popliteal fossa immediately after lymphadenectomy failed to survive.10 However, when the medulla of a popliteal lymph node was enucleated and its blood supply ligated, leaving the afferent and efferent lymphatics intact, the lymph node survived and the medulla regenerated. They concluded that maintenance of the vascular supply of the transplanted lymph node will ensure its viability, but whether such a transplanted lymph node would reform connections with afferent and efferent lymphatics remains to be demonstrated. In a landmark experiment on rats, Shesol et al. showed that transplanted lymph nodes survived and remained functional, provided that their vascular supply was maintained and there was an “open” lymphatic system at the recipient site.11 When the groin lymph node flap was transferred to the lymphadenectomized popliteal fossa as either an island flap or a free flap, it survived and reintegrated into the lymphatic circulation. However, when the vascular pedicle was divided and the tissue transferred as a graft, it did not survive. Similarly, when the groin island flaps were transferred to the popliteal fossa of animals that did not have lymphadenectomy, the transferred lymph nodes failed to integrate into the recipient site’s lymphatic circulation, supporting the requirement for an open lymphatic system. Unfortunately, this experiment is frequently referenced as supporting evidence for vascularized lymph node transfer in the treatment of chronic lymphedema, disregarding the above prerequisite. In the same experiment, the success of lymph node transfer was significantly less when it was
Table 1. Summary of Experimental Studies on Lymph Node Transfer Study
Species
Jaffe and Richter, 19284
Lymphedema Model
Didukh, 19675 Pabst and Rothkötter, 19886 Blum et al., 20077 Fu et al., 19988 Blum et al., 20109 Tilak and Howard, 196510
Guinea pigs Rats Mice Minipigs Minipigs Rabbits Minipigs Frogs
Acute Acute Acute Acute Acute Acute Acute Acute
Shesol et al., 197911
Rats
Acute
Chen et al., 1990 Tobbia et al., 200913
Dogs Sheep
Chronic Acute
Tammela et al., 200714 Lähteenvuo et al., 201115 Aschen et al., 201416 Joseph et al., 201417
Mice Pigs Mice Mice
Acute Acute Acute Acute
12
Transferred Tissue
Vascularized?
Successful Take?
Intact LN Intact LN Intact LN LN fragments LN fragments LN fragments LN fragments LN fragments Intact LN LN flap LN flap LN flap Intact LN LN flap LN fragments Intact LN Intact LN Intact LN
No No No No No No No No Yes No Yes Yes No Yes No Yes No No
No Yes Yes Yes Yes Yes Yes No Yes No Yes Yes * Yes Yes Yes Yes Yes
LN, lymph node. *Successful take of LN indicated by histologic grade of 2–3 was seen in only two of 12 in the avascularized group vs. six of 10 in the vascularized group.
986 Copyright © 2016 American Society of Plastic Surgeons. Unauthorized reproduction of this article is prohibited.
Volume 137, Number 3 • Vascularized Lymph Node Transfer delayed for 2 to 7 days after lymphadenectomy (33 percent) compared with immediate transfer (80 percent), possibly explained by the reduced availability of open lymphatic channels. Chen et al. examined the efficacy of vascularized lymph node transfer in chronic lymphedema in a canine model.12 Stable below-knee lymphedema was established in dogs by irradiation and circumferential skin excision at the knee, followed by popliteal lymphadenectomy. A free groin lymph node flap with abundant perinodal tissue was transferred to the popliteal fossa and inset to bridge the zone of dense fibrosis between the proximal and distal normal tissues. A statistically significant reduction in excess limb circumference was seen at 3 months; however, none of the limbs returned to normal size at the 6-month follow-up. Postoperative lymphangiography demonstrated spontaneous recanalization of the lymphatic channels with drainage across the obstructed zone, but no comment was made on visualization of the transferred lymph nodes. Postoperative lymphoscintigraphy showed uptake of the radiotracer by the transferred lymph node and liver, but it was not quantified. Tobbia et al. compared the effect of vascularized versus avascular lymph node transfer in an ovine model.13 Lymphatic function 8 to 12 weeks after transfer was significantly higher in the vascularized group. Similarly, postoperative edema was less in the vascularized versus avascular lymph node transfer group; however, it failed to register significance. Vascular endothelial growth factor (VEGF)-C is recognized as the principal regulator of lymphangiogenesis.19 Administration of exogenous VEGF-C has been shown to improve functional integration of transferred avascular and vascularized lymph nodes in animal models.14,15 However, some concerns have been raised regarding the use of VEGF-C in cancer patients, as it may enhance tumor growth and metastasis.20,21 Other experiments have shown that expression of endogenous VEGF-C is markedly raised at the sites of lymphangiogenesis and that it can be further enhanced by induction of a sterile inflammatory response after lymph node transfer.16,17,22 In summary, there is good evidence to suggest that avascular lymph node fragments autotransplanted into suitable recipient sites will regenerate into lymphoid tissues. Maintaining vascularization of the transferred lymph nodes ensures their survival and is essential when a lymph node–bearing block of tissue is transferred. There is also good experimental evidence to suggest that the
transferred lymph nodes are able to integrate with the recipient site’s lymphatic circulation soon after its disruption. However, two fundamental questions remain unanswered: 1. What is the efficacy of lymph drainage across the transferred lymphatic tissue? This question could only be addressed by experiments in which a sustained lymph stasis was generated and then the effect of transfer on edema was compared with a control group. The experiments by Fu et al. on rabbits’ ears and by Chen et al. on dogs’ legs improved the edema but failed to completely resolve it.8,12 In the experiment by Tobbia et al. on sheep, a sustained edema was not generated, and in all groups the edema improved over the course of the study, although this was quicker in the vascularized lymph node transfer group.13 2. Will the transferred lymph nodes integrate with the recipient site’s lymphatics that are affected by chronic lymphedema? The only chronic lymphedema model was the canine model used by Chen et al. in which a large lymphatic-rich flap was used to bridge the entire zone of lymphatic obstruction.12 However, in clinical cases of chronic lymphedema, the zone of lymphatic abnormality has often extended distally much beyond the initial lymphadenectomy zone, which cannot be traversed by the lymph node flap.23 This reduces the availability of “open” lymphatic channels as pointed out by Shesol et al.11
FUNCTIONAL MECHANISMS Two main hypotheses have been proposed to explain the potential functional mechanism of vascularized lymph node transfer in chronic lymphedema (Fig. 1). One proposed mechanism is that the lymph node flap is naturally rich with lymphatic collectors and simply acts as a lymphatic wick to bridge the zone of obstruction. The concept of lymphatic wick is not new in the history of reconstructive lymphatic surgery. Surgeons have used silk threads, fascial strips, omentum, or skin flaps to treat lymphedema by this mechanism.24 For a lymphatic flap to function as an effective wick, two requirements must be met. First, the flap must bridge the entire zone of obstruction, with functional lymphatics present proximally and distally at the recipient site. Clinically, this is possible when the vascularized lymph
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Plastic and Reconstructive Surgery • March 2016
Fig. 1. Schematic diagram showing the two theories on the functional mechanism of vascularized lymph node transfer. In both theories, spontaneous anastomosis between the afferent lymphatics of the donor site and the transferred lymph nodes is required. In the lymphatic wick theory (left), spontaneous anastomosis between the lymph nodes and the efferent lymphatics of the recipient site is required to bridge the lymphatic gap. In the lymphatic pump theory (right), the intrinsic lymphovenous shunts within the transferred lymph nodes is responsible for redirecting the lymph load to the venous circulation.
node transfer is performed immediately after lymph node dissection or at the very early stages of lymphedema. Second, spontaneous lympholymphatic anastomosis must form between the donor and recipient lymphatics at the proximal and distal stump that can effectively drain the lymphatic load of the limb. It has been suggested that the transferred lymph nodes may act as an endogenous source of VEGF-C that augments lymphangiogenesis after transfer25; however, solid scientific evidence to support this hypothesis is lacking. As mentioned above, although reintegration into the recipient lymphatics has been shown, the efficiency of these connections is yet to be examined. The other proposed mechanism is that the lymph node–bearing flap transferred to the distal extremity acts as a lymphatic pump by absorbing the interstitial fluid that has gravitated down the limb and shifting it into the systemic circulation by means of the intrinsic lymphovenous shunt within the nodes. It has been shown that approximately 50 to 66 percent of the lymph is resorbed back to the systemic circulation within the lymph nodes.26 In a study by Cheng et al., when indocyanine green was injected into the edges of the lymph node flaps,
it was quickly seen in the donor vein and then in the recipient vein.27 However, when it was injected into the subcutaneous fat of the deep inferior epigastric artery perforator flap, it failed to distribute. They concluded that the indocyanine green was absorbed by the transferred lymph nodes within the flap and drained into the donor vein through its native lymphovenous shunt. This observation, although interesting, is not conclusive. First, their findings can be alternatively explained by the known rich blood supply of the nodes and perinodal tissues compared with the relatively low blood supply of the subcutaneous fat. Absorption of the indocyanine green by the blood capillaries of the donor tissue could have produced the same result. Second, the manner by which the lymph gains entry into the node is not very clear in this proposed mechanism. It is known that the afferent collectors are not absorptive vessels. Lymph absorption only occurs at the level of capillary lymphatics and to a limited extent by the precollectors.28 In his microlymphangiographic studies on rabbit ear models, Oden showed that newly formed capillary lymphatics sprouted out from the severed ends of collectors and eventually joined with the other
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Volume 137, Number 3 • Vascularized Lymph Node Transfer collectors in the vicinity.29 However, this cannot explain absorption of lymph into the node immediately after surgery. Recently, Aschen et al., in an innovative experiment on an acute lymphedema model in transgenic mice, were able to show massive infiltration of recipient lymphatics into the transferred lymph nodes, spontaneous anastomosis between the recipient and donor lymphatics, and close proximity of the lymphatics to the high endothelial venules of the lymph nodes.16 It will be interesting to see whether these results can be reproduced in a chronic lymphedema model.
CLINICAL EXPERIENCE WITH VASCULARIZED LYMPH NODE TRANSFER Table 23,25,30–34 summarizes study methodologies of the published clinical series on vascularized lymph node transfer. Although improvement in lymphedema symptoms has been reported in most studies, the level of evidence to advocate this procedure in the treatment of chronic lymphedema remains low because of the small number of cases and problems in their methodologies, as follows: 1. Patient selection: Lymphedema is a chronic progressive condition that is characterized by chronic lymph stasis, which eventually leads to fibrosis and adipose hypertrophy of the subcutaneous tissues.35,36 Successful restoration of the normal limb volume by any of the available physiologic procedures directly depends on the proportional degree of the latter irreversible changes. The published case series included a heterogeneous group of patients with a wide range of duration and severity of lymphedema. In the future, the use of advanced imaging modalities including magnetic resonance imaging and indocyanine green lymphography can improve preoperative staging and patient selection.37–39 2. Conservative therapy: It is possible that patients who have chosen surgery for their lymphedema are more motivated in their treatment. Such patients may also be more likely to be compliant with their prescribed postoperative physiotherapy regimen, which can confound interpretation of the results. Selecting patients who are on a stable complete decongestive therapy regimen preoperatively and postoperatively can potentially eliminate this confounding factor. Patients can then be gradually weaned off complete decongestive therapy depending on their response.
3. Outcome measures: a. Subjective assessment of lymphedema symptoms reported by patients is unreliable; to quote Puckett: “These unfortunate and usually neglected (lymphedema) patients are delighted to find an interested, caring, and enthusiastic physician, and they will reliably ‘do better’ for us regardless of their status of objective improvement.”40 b. Circumference measurements used by the published series notoriously lack reliability in monitoring lymphedema volume.41 Volume displacement remains the gold standard but is inconvenient for both patients and researchers. Alternatively, perimetric measures with 5- to 10-cm increments can be put in the truncated cone formula to calculate the limb volume, which closely correlates with the volume displacement method and has been shown to have excellent interobserver and intraobserver reproducibility.42,43 c. Quantitative assessment of lymphatic function with lymphoscintigraphy has been regularly used in experimental studies of lymph node transfer. In the published clinical series, although lymphoscintigraphy was often performed, a systematic quantitative analysis was missing. d. Other methods such as bioelectrical impedance analysis,44 tissue tonometry,45 and magnetic resonance imaging46 can be used to more objectively monitor the therapeutic response. 4. Follow-up: Clinical lymphedema occurs when the lymph load of an extremity exceeds its lymph transport capacity. Therefore, even complete postoperative resolution of edema—unless the transport capacity is fully restored—does not mean that the procedure has cured the condition, but at best has returned lymphedema to its latent phase. With time, the remaining collectors overloaded with lymph will decompensate and clinical edema will recur.24,47 Therefore, long-term follow-up is required to assess the efficacy of vascularized lymph node transfer in the treatment of chronic lymphedema. 5. Study design: Most published studies to date are uncontrolled case series with small numbers. High-quality randomized controlled studies are needed to conclusively endorse or repudiate this procedure.
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10 Cheng et al.. 201333
LS, lymphoscintigraphy; ISL, International Society of Lymphology. *International Society of Lymphology. The diagnosis and treatment of peripheral lymphedema: 2009 Consensus Document of the International Society of Lymphology. Lymphology 2009:42:51–60.
III Prospective controlled 39.1 ± 15.7 mo
9 Saaristo et al., 201225
Three times per week for 1 mo then twice weekly for 2 mo Nil
Subjective patient survey, rate of cellulitis, limb circumference
IV Prospective 8–24 mo
IV
Subjective patient survey, rate of cellulitis, limb Circumference, Limb circumference, quantitative LS 7 Cheng et al., 201232
Not routinely used
36–120 mo duration, stage II and III (ISL)*, treatment resistant 6–120 mo duration, excluding longstanding severe edema 12–84 mo duration, stage II (ISL)*
21 Gharb et al., 201131
No comment Early stage II (ISL)*, resistant to at least 6 mo of conservative therapy
13 Lin et al., 200930
No comment
Prospective
IV Retrospective
Standard group: 26–120 mo (46 mo) Hilar group: 38–50 mo (40 mo) 2–22 mo (8.7 mo)
IV Prospective 6–96 mo (56.3)
IV Retrospective 5–11 yr (8.3 yr)
Rate of cellulitis, limb circumference, qualitative LS Subjective patient survey, limb circumference, qualitative LS Subjective patient survey, rate of cellulitis, limb circumference Daily for 3 mo then biweekly for 3 mo
3 mo–15 yr duration, treatment resistant, excluding elephantiasis 4–84 mo duration 24 Becker et al., 20063
Follow-Up (Mean) Outcome Measures Postoperative Physiotherapy Lymphedema Severity No. of Patients Study
Table 2. Summary of Study Methodologies of Published Clinical Series on Vascularized Lymph Node Transfer
Study Design
Level of Evidence
Plastic and Reconstructive Surgery • March 2016 RISK OF IATROGENIC LYMPHEDEMA The most frequently used donor site in vascularized lymph node transfer is the groin, where the superolateral superficial inguinal lymph nodes are harvested on the superficial circumflex iliac artery or the superficial inferior epigastric artery. Its familiar anatomy, a hidden cosmetic scar, and its capacity to be raised in continuity with abdominal flaps for autologous breast reconstruction have made the groin the most suitable donor site for breast cancer–related secondary lymphedema. Although the groin flap has been used for many years with no reports of iatrogenic lymphedema in the donor limb, some concerns have been raised recently with regard to the safety of this flap in patients with lymphedema.48–50 Two factors can possibly explain the emergence of these concerning reports. First, lymphedema is a notoriously underdiagnosed condition.51 The increased awareness of lymphedema as a complication in both the patient and the treating surgeon after vascularized lymph node transfer is likely to facilitate its diagnosis. In contrast, unless they are proactively sought, the signs and symptoms of lymphedema are more likely to be missed in a grateful patient following a life- or limb-saving groin flap procedure. Second, patients with secondary lymphedema may be constitutionally predisposed to this condition.52–55 Although the reduction in lymphatic drainage of the donor limb may be well tolerated in a patient with normal lymphatic function, it may lead to lymphedema in patients with constitutionally reduced lymph transport capacity. Therefore, it is of utmost importance to preserve the lymphatic function of the donor site in these patients. The nodes of interest in the groin lymph node flap are the superolateral group of the superficial inguinal lymph nodes that are located along the superficial circumflex iliac vein (Fig. 2). In contrast, cadaveric, direct lymphangiography, and single-photon emission computed tomographic studies have shown that the primary superficial nodes draining the lower limb are located just below the saphenofemoral junction (located at the groin crease) and medial to the femoral artery.56–58 Therefore, to preserve the lymphatic function of the lower limb when harvesting the groin lymph node flap, it is crucial to dissect superficial to the deep fascia and limit the medial and inferior borders of the dissection to the femoral artery and the groin crease, respectively. In addition to these anatomical landmarks, Dayan et al. suggested reverse lymphatic mapping using a combination of indocyanine green lymphography
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Volume 137, Number 3 • Vascularized Lymph Node Transfer nodes were the primary nodes draining the local collectors of the thigh; the latter originate from the watershed area of the posterior thigh.61,62 Therefore, even careful selection of these nodes may marginally affect the lymphatic function of the lower limb, which theoretically in the long term may lead to clinical lymphedema in a small percentage of patients. Alternative donor sites including submental, axillary, and supraclavicular flaps are mainly used in cancer-related secondary lymphedema of the lower limbs, where the groin lymph nodes are not available because of surgery, radiation therapy, and other factors. The development of contralateral axillary lymph node metastases following the treatment of unilateral breast cancer in 3.6 to 6 percent of cases discourages use of axillary lymph nodes in patients with breast cancer.9 The unsightly scars and the possibility of nerve injuries disadvantage the neck donor sites. Anatomical studies are currently underway to examine the details of these and potential new donor lymphatic tissues. Fig. 2. Topographically, the superficial inguinal lymph nodes are divided into five zones by a horizontal line and a vertical line intersecting at the saphenous bulb (Daseler EH, Anson BJ, Reimann AF. Radical excision of the inguinal and iliac lymph glands; a study based upon 450 anatomical dissections and upon supportive clinical observations. Surg Gynecol Obstet. 1948;87:679–694.): the superomedial group (SM) associated with the superficial epigastric vein (1), the inferomedial group (IM) associated with the superficial external pudendal veins (2), the inferolateral group (IL) associated with the great saphenous vein (3) and the lateral accessory saphenous vein (4), the superolateral group located along the superficial circumflex iliac vein (5), and the central group (C) located over the saphenous bulb. The nodes of interest in vascularized lymph node transfer with a groin donor site are the superolateral (SL) group. When harvesting the groin lymph node flap for vascularized lymph node transfer, the dissection should stay lateral to the femoral artery (shown in red) and proximal to the groin crease. The danger zone (shaded in orange) must be avoided in order to preserve the lymphatic function of the lower limb.
and lymphoscintigraphy to more precisely guide flap harvest in individual patients.59 It should be noted that although the superolateral group of the superficial inguinal lymph nodes are mainly involved with the drainage of the lower abdomen, lower back, and the upper gluteal region, this is not exclusive. Caplan studied the lymphatic drainage of the great toe in 50 human fetuses and found drainage to these nodes in nine cases.60 In another study in patents with malignant melanoma of the lower limb, the sentinel node was located in the superolateral zone in 5 percent of the cases.58 Direct injection studies in adult human cadavers by the current authors revealed that the superolateral
SUMMARY Neither of the proposed functional mechanisms of vascularized lymph node transfer is strongly supported by the available experimental evidence, and more basic research is needed on chronic lymphedema models. The initial results of vascularized lymph node transfer in the treatment of chronic lymphedema have been promising thus far. However, the level of evidence to support this procedure as the standard therapy for chronic lymphedema remains low, and longterm well-designed studies are required. Further anatomical studies to explore potential new donor sites are needed, and it is crucial that iatrogenic chronic morbidities are not caused in the interim. Saam S. Tourani, M.D. Department of Anatomy and Neuroscience University of Melbourne Room E533 Medical Building Grattan Street Parkville, Victoria 3010, Australia [email protected]
ACKNOWLEDGMENTS
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Plastic and Reconstructive Surgery • March 2016 women of working age: A 2-year follow-up study. J Clin Oncol. 2009;27:2007–2014. 3. Becker C, Assouad J, Riquet M, Hidden G. Postmastectomy lymphedema: Long-term results following microsurgical lymph node transplantation. Ann Surg. 2006;243:313–315. 4. Jaffe HL, Richter MN. The regeneration of autoplastic lymph node transplants. J Exp Med. 1928;47:977–980. 5. Didukh MS. Regeneration of transplanted lymph glands (in Russian). Biull Eksp Biol Med. 1967;64:84–88. 6. Pabst R, Rothkötter HJ. Regeneration of autotransplanted lymph node fragments. Cell Tissue Res. 1988;251:597–601. 7. Blum KS, Radtke C, Knapp WH, Pabst R, Gratz KF. SPECT-CT: A valuable method to document the regeneration of lymphatics and autotransplanted lymph node fragments. Eur J Nucl Med Mol Imaging 2007;34:1861–1867. 8. Fu K, Izquierdo R, Vandevender D, Warpeha RL, Fareed J. Transplantation of lymph node fragments in a rabbit ear lymphedema model: A new method for restoring the lymphatic pathway. Plast Reconstr Surg. 1998;101:134–141. 9. Blum KS, Hadamitzky C, Gratz KF, Pabst R. Effects of autotransplanted lymph node fragments on the lymphatic system in the pig model. Breast Cancer Res Treat. 2010;120:59–66. 10. Tilak SP, Howard JM. Regeneration and autotransplantation of lymph nodes. Ann Surg. 1965;161:441–446. 11. Shesol BF, Nakashima R, Alavi A, Hamilton RW. Successful lymph node transplantation in rats, with restoration of lymphatic function. Plast Reconstr Surg. 1979;63:817–823. 12. Chen HC, O’Brien BM, Rogers IW, Pribaz JJ, Eaton CJ. Lymph node transfer for the treatment of obstructive lymphoedema in the canine model. Br J Plast Surg. 1990;43:578–586. 13. Tobbia D, Semple J, Baker A, Dumont D, Johnston M. Experimental assessment of autologous lymph node transplantation as treatment of postsurgical lymphedema. Plast Reconstr Surg. 2009;124:777–786. 14. Tammela T, Saaristo A, Holopainen T, et al. Therapeutic differentiation and maturation of lymphatic vessels after lymph node dissection and transplantation. Nat Med. 2007;13:1458–1466. 15. Lähteenvuo M, Honkonen K, Tervala T, et al. Growth factor therapy and autologous lymph node transfer in lymphedema. Circulation 2011;123:613–620. 16. Aschen SZ, Farias-Eisner G, Cuzzone DA, et al. Lymph node transplantation results in spontaneous lymphatic reconnection and restoration of lymphatic flow. Plast Reconstr Surg. 2014;133:301–310. 17. Joseph WJ, Aschen S, Ghanta S, et al. Sterile inflammation after lymph node transfer improves lymphatic function and regeneration. Plast Reconstr Surg. 2014;134:60–68. 18. Daoud J, Meziou M, Kharrat M, Sellami D, Boudawara T, Frikha M. Contralateral axillary lymph node metastasis of cancer of the breast (in French). Bull Cancer 1998;85:713–715. 19. Tilak SP, Howard JM. the influence of the dual circulation on the viability of lymph nodes following interruption of their blood or lymphatic supply. Surg Gynecol Obstet. 1964;119:349–352. 20. Jeltsch M, Kaipainen A, Joukov V, et al. Hyperplasia of lymphatic vessels in VEGF-C transgenic mice. Science 1997;276:1423–1425. 21. Skobe M, Hawighorst T, Jackson DG, et al. Induction of tumor lymphangiogenesis by VEGF-C promotes breast cancer metastasis. Nat Med. 2001;7:192–198. 22. Das S, Ladell DS, Podgrabinska S, et al. Vascular endothelial growth factor-C induces lymphangitic carcinomatosis, an extremely aggressive form of lung metastases. Cancer Res. 2010;70:1814–1824. 23. Yan A, Avraham T, Zampell JC, Aschen SZ, Mehrara BJ. Mechanisms of lymphatic regeneration after tissue transfer. PLoS One 2011;6:e17201.
24. Koshima I, Kawada S, Moriguchi T, Kajiwara Y. Ultrastructural observations of lymphatic vessels in lymphedema in human extremities. Plast Reconstr Surg. 1996;97:397–405; discussion 406. 25. Clodius L. Lymphedema. In: McCarthy J, ed. Plastic and Reconstructive Surgery. 3rd ed. Philadelphia: Saunders; 1990: 4110–4120. 26. Saaristo AM, Niemi TS, Viitanen TP, Tervala TV, Hartiala P, Suominen EA. Microvascular breast reconstruction and lymph node transfer for postmastectomy lymphedema patients. Ann Surg. 2012;255:468–473. 27. Renkin EM. Some consequences of capillary permeability to macromolecules: Starling’s hypothesis reconsidered. Am J Physiol. 1986;250:H706–H710. 28. Cheng MH, Huang JJ, Wu CW, et al. The mechanism of vascularized lymph node transfer for lymphedema: Natural lymphaticovenous drainage. Plast Reconstr Surg. 2014;133:192e–198e. 29. Ryan T. The lymphatics of the skin. In: The Physiology and Pathophysiology of the Skin. London: Academic Press; 1978: 1755–1780. 30. Oden B. A micro-lymphangiographic study of experimental wounds healing by second intention. Acta Chir Scand. 1960;120:100–114. 31. Lin CH, Ali R, Chen SC, et al. Vascularized groin lymph node transfer using the wrist as a recipient site for management of postmastectomy upper extremity lymphedema. Plast Reconstr Surg. 2009;123:1265–1275. 32. Gharb BB, Rampazzo A, Spanio di Spilimbergo S, Xu ES, Chung KP, Chen HC. Vascularized lymph node transfer based on the hilar perforators improves the outcome in upper limb lymphedema. Ann Plast Surg. 2011;67:589–593. 33. Cheng MH, Huang JJ, Huang JJ, et al. A novel approach to the treatment of lower extremity lymphedema by transferring a vascularized submental lymph node flap to the ankle. Gynecol Oncol. 2012;126:93–98. 34. Cheng MH, Chen SC, Henry SL, Tan BK, Lin MC, Huang JJ. Vascularized groin lymph node flap transfer for postmastectomy upper limb lymphedema: Flap anatomy, recipient sites, and outcomes. Plast Reconstr Surg. 2013;131:1286–1298. 35. International Society of Lymphology. The diagnosis and treatment of peripheral lymphedema: 2009 Consensus Document of the International Society of Lymphology. Lymphology 2009;42:51–60. 36. Brorson H. From lymph to fat: Complete reduction of lymphoedema. Phlebology 2010;25(Suppl 1):52–63. 37. Zampell JC, Aschen S, Weitman ES, et al. Regulation of adipogenesis by lymphatic fluid stasis: Part I. Adipogenesis, fibrosis, and inflammation. Plast Reconstr Surg. 2012;129:825–834. 38. Aström KG, Abdsaleh S, Brenning GC, Ahlström KH. MR imaging of primary, secondary, and mixed forms of lymphedema. Acta Radiol. 2001;42:409–416. 39. Yamamoto T, Yamamoto N, Doi K, et al. Indocyanine greenenhanced lymphography for upper extremity lymphedema: A novel severity staging system using dermal backflow patterns. Plast Reconstr Surg. 2011;128:941–947. 40. Yamamoto T, Yamamoto N, Hara H, Mihara M, Narushima M, Koshima I. Upper extremity lymphedema index: A simple method for severity evaluation of upper extremity lymphedema. Ann Plast Surg. 2013;70:47–49. 41. Puckett CL. Microlymphaticovenous anastomosis in the treatment of lower-limb obstructive lymphedema: Analysis of 91 cases (Discussion). Plast Reconstr Surg. 1985;76:678–679. 42. Stillwell G. Management of arm edema. In: Stoll B, ed. Breast Cancer Management: Early and Late. London: Heinemann; 1977: 213–224.
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Volume 137, Number 3 • Vascularized Lymph Node Transfer 43. Galland C, Auvert JF, Flahault A, Vayssairat M. Why and how post-mastectomy edema should be quantified in patients with breast cancer. Breast Cancer Res Treat. 2002;75:87–89. 44. Kaulesar Sukul DM, den Hoed PT, Johannes EJ, van Dolder R, Benda E. Direct and indirect methods for the quantification of leg volume: Comparison between water displacement volumetry, the disk model method and the frustum sign model method, using the correlation coefficient and the limits of agreement. J Biomed Eng. 1993;15:477–480. 45. Ward LC. Bioelectrical impedance analysis: Proven utility in lymphedema risk assessment and therapeutic monitoring. Lymphat Res Biol. 2006;4:51–56. 46. Bates DO, Levick JR, Mortimer PS. Quantification of rate and depth of pitting in human edema using an electronic tonometer. Lymphology 1994;27:159–172. 47. Idy-Peretti I, Bittoun J, Alliot FA, Richard SB, Querleux BG, Cluzan RV. Lymphedematous skin and subcutis: In vivo high resolution magnetic resonance imaging evaluation. J Invest Dermatol. 1998;110:782–787. 48. Modi S, Stanton AW, Svensson WE, Peters AM, Mortimer PS, Levick JR. Human lymphatic pumping measured in healthy and lymphoedematous arms by lymphatic congestion lymphoscintigraphy. J Physiol. 2007;583:271–285. 49. Viitanen TP, Mäki MT, Seppänen MP, Suominen EA, Saaristo AM. Donor-site lymphatic function after microvascular lymph node transfer. Plast Reconstr Surg. 2012;130:1246–1253. 50. Vignes S, Blanchard M, Yannoutsos A, Arrault M. Complications of autologous lymph-node transplantation for limb lymphoedema. Eur J Vasc Endovasc Surg. 2013;45:516–520. 51. Pons G, Masia J, Loschi P, Nardulli ML, Duch J. A case of donor-site lymphoedema after lymph node-superficial circumflex iliac artery perforator flap transfer. J Plast Reconstr Aesthet Surg. 2014;67:119–123. 52. Hayes S, Janda M, Cornish B, Battistutta D, Newman B. Lymphedema secondary to breast cancer: How choice of
measure influences diagnosis, prevalence, and identifiable risk factors. Lymphology 2008;41:18–28. 53. Newman B, Lose F, Kedda MA, et al. Possible genetic predisposition to lymphedema after breast cancer. Lymphat Res Biol. 2012;10:2–13. 54. Finegold DN, Baty CJ, Knickelbein KZ, et al. Connexin 47 mutations increase risk for secondary lymphedema following breast cancer treatment. Clin Cancer Res. 2012;18:2382–2390. 55. Aldrich MB, Guilliod R, Fife CE, et al. Lymphatic abnormalities in the normal contralateral arms of subjects with breast cancer-related lymphedema as assessed by near-infrared fluorescent imaging. Biomed Opt Express 2012;3:1256–1265. 56. Mellor RH, Stanton AW, Azarbod P, Sherman MD, Levick JR, Mortimer PS. Enhanced cutaneous lymphatic network in the forearms of women with postmastectomy oedema. J Vasc Res. 2000;37:501–512. 57. Daseler EH, Anson BJ, Reimann AF. Radical excision of the inguinal and iliac lymph glands; a study based upon 450 anatomical dissections and upon supportive clinical observations. Surg Gynecol Obstet. 1948;87:679–694. 58. Bruna J. Clinical Lymphography. Prague: Avicenum; 1977. 59. van der Ploeg IM, Kroon BB, Valdés Olmos RA, Nieweg OE. Evaluation of lymphatic drainage patterns to the groin and implications for the extent of groin dissection in melanoma patients. Ann Surg Oncol. 2009;16:2994–2999. 60. Dayan JH, Dayan E, Kagen A, et al. The use of magnetic resonance angiography in vascularized groin lymph node transfer: An anatomic study. J Reconstr Microsurg. 2014;30:41–45. 61. Caplan I. The lymphatic system of the big toe: A study and investigation about 50 cases. Folia Angiol. 1978;26:241–245. 62. Tourani SS, Taylor GI, Ashton MW. Anatomy of the superficial lymphatics of the abdominal wall and the upper thigh and its implications in lymphatic microsurgery. J Plast Reconstr Aesthet Surg. 2013;66:1390–1395. 63. Tourani SS, Taylor GI, Ashton MW. Understanding the three-dimensional anatomy of the superficial lymphatics of the limbs. Plast Reconstr Surg. 2014;134:1065–1074.
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Summary: Over the past decade, lymph node transfer has rapidly gained popularity among plastic surgeons for the treatment of chronic lymphedema because of the initial promising results and its unique technical advantages compared with the other reconstructive options. However, its functional mechanism is still a matter of great debate, and some concerning reports have emerged regarding the safety of this procedure in patients with chronic lymphedema. The authors review the literature on the experimental and clinical evidence for lymph node transfer, discuss its proposed functional mechanisms, review the potential risk of iatrogenic lymphedema following this procedure, and discuss the suggested strategies to avoid this complication. (Plast. Reconstr. Surg. 137: 985, 2016.)
L
ymphedema is a chronic progressive condition in which accumulation of high-protein fluid in the interstitium induces cellular proliferation and inflammation that results in thickening and fibrosis of lymphatic vessels and surrounding tissue.1 Currently, there is no cure for this condition. The standard treatment is complete decongestive therapy that aims to improve the physical characteristics of the limb, alleviate symptoms, and reduce disease progression and secondary complications. Although effective in many patients, complete decongestive therapy is time consuming, difficult to perform on regular basis, and expensive.2 These barriers, together with a shortage of trained lymphedema therapists, lead to high rates of noncompliance and patient dissatisfaction. Surgical procedures for lymphedema are generally considered in two categories. Reductive methods such as direct excision or liposuction aim to remove the fibrofatty tissue that has been generated as a consequence of sustained lymph stasis. In contrast, physiologic (reconstructive) methods such as vascularized lymph node transfer and lymphovenous anastomosis aim to improve/restore the lymphatic drainage of the affected limb. In vascularized lymph node transfer, lymph nodes are harvested from a donor site and transferred as a free flap to the lymphedematous limb. Currently, two main hypotheses are postulated to From the Department of Anatomy and Neuroscience, University of Melbourne. Received for publication May 24, 2015; accepted October 26, 2015. Copyright © 2016 by the American Society of Plastic Surgeons DOI: 10.1097/01.prs.0000475827.94283.56
explain the functional mechanism of this procedure (i.e., the lymphatic wick and the lymphatic pump theory), with arguable experimental evidence available to support either one. Nevertheless, it has rapidly gained popularity among plastic surgeons since Becker et al. reported the first clinical series nearly a decade ago.3 This growing enthusiasm can perhaps be explained by both the initial promising results and some favorable technical factors associated with this procedure: 1. It is technically less challenging than lymphovenous anastomosis, as no lymphatic anastomosis is required. 2. It can be performed in more advanced cases of lymphedema where no suitable lymphatics can be found for lymphovenous anastomosis. 3. It can be performed in continuity with the deep inferior epigastric artery perforator flap for breast reconstruction. In this article, we first review the experimental evidence behind lymph node transfer. Second, the proposed functional mechanisms of vascularized lymph node transfer are discussed in view of the available evidence. Third, a brief summary of the published clinical series is given followed by a critical appraisal of their methodology. Fourth, the potential risk of iatrogenic lymphedema following this procedure and the suggested measures to avoid this complication are reviewed. Disclosure: The authors have no financial interest to declare in relation to the content of this article.
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Plastic and Reconstructive Surgery • March 2016 EXPERIMENTAL STUDIES Table 14–17 provides a summary of experimental studies on lymph node transfer. The earliest experiment is often credited to Jaffe and Richter in 1928.4 Although their experiment on stock guinea pigs failed because of infection, planting of intact cervical lymph nodes into the abdominal wall muscle of albino rats led to 90 percent take with complete regeneration of nodal architecture by day 6. Didukh reported 70 percent take following subcutaneous implantation of the intact lymph nodes in mice.5 Pabst and Rothkötter showed that transplanted lymph node fragments into the groin of minipigs not only regenerated into lymph node-like structures but also were integrated into the lymphatic drainage of the hind limb.6 In a similar experiment, Blum et al. used single-photon emission computed tomographic imaging to successfully demonstrate reintegration of lymph node fragments into the groin lymphatic drainage of minipigs.7 The above results generated hope for successfully using avascular autologous lymph node transplant to treat lymphedema. Fu et al. transferred lymph node fragments to an established lymphedema model in rabbit ears.8 Indirect lymphangiography 5 months postoperatively showed improved lymphatic drainage in the transplant group, with no dermal backflow. Although volume measurements showed significantly more volume reduction in the transplant group, the normal volumes were not achieved. In contrast, Tilak and Howard emphasized the importance of lymph node dual vascular supply on its viability.18 In their experiments on dogs,
lymph node fragments grafted into the popliteal fossa immediately after lymphadenectomy failed to survive.10 However, when the medulla of a popliteal lymph node was enucleated and its blood supply ligated, leaving the afferent and efferent lymphatics intact, the lymph node survived and the medulla regenerated. They concluded that maintenance of the vascular supply of the transplanted lymph node will ensure its viability, but whether such a transplanted lymph node would reform connections with afferent and efferent lymphatics remains to be demonstrated. In a landmark experiment on rats, Shesol et al. showed that transplanted lymph nodes survived and remained functional, provided that their vascular supply was maintained and there was an “open” lymphatic system at the recipient site.11 When the groin lymph node flap was transferred to the lymphadenectomized popliteal fossa as either an island flap or a free flap, it survived and reintegrated into the lymphatic circulation. However, when the vascular pedicle was divided and the tissue transferred as a graft, it did not survive. Similarly, when the groin island flaps were transferred to the popliteal fossa of animals that did not have lymphadenectomy, the transferred lymph nodes failed to integrate into the recipient site’s lymphatic circulation, supporting the requirement for an open lymphatic system. Unfortunately, this experiment is frequently referenced as supporting evidence for vascularized lymph node transfer in the treatment of chronic lymphedema, disregarding the above prerequisite. In the same experiment, the success of lymph node transfer was significantly less when it was
Table 1. Summary of Experimental Studies on Lymph Node Transfer Study
Species
Jaffe and Richter, 19284
Lymphedema Model
Didukh, 19675 Pabst and Rothkötter, 19886 Blum et al., 20077 Fu et al., 19988 Blum et al., 20109 Tilak and Howard, 196510
Guinea pigs Rats Mice Minipigs Minipigs Rabbits Minipigs Frogs
Acute Acute Acute Acute Acute Acute Acute Acute
Shesol et al., 197911
Rats
Acute
Chen et al., 1990 Tobbia et al., 200913
Dogs Sheep
Chronic Acute
Tammela et al., 200714 Lähteenvuo et al., 201115 Aschen et al., 201416 Joseph et al., 201417
Mice Pigs Mice Mice
Acute Acute Acute Acute
12
Transferred Tissue
Vascularized?
Successful Take?
Intact LN Intact LN Intact LN LN fragments LN fragments LN fragments LN fragments LN fragments Intact LN LN flap LN flap LN flap Intact LN LN flap LN fragments Intact LN Intact LN Intact LN
No No No No No No No No Yes No Yes Yes No Yes No Yes No No
No Yes Yes Yes Yes Yes Yes No Yes No Yes Yes * Yes Yes Yes Yes Yes
LN, lymph node. *Successful take of LN indicated by histologic grade of 2–3 was seen in only two of 12 in the avascularized group vs. six of 10 in the vascularized group.
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Volume 137, Number 3 • Vascularized Lymph Node Transfer delayed for 2 to 7 days after lymphadenectomy (33 percent) compared with immediate transfer (80 percent), possibly explained by the reduced availability of open lymphatic channels. Chen et al. examined the efficacy of vascularized lymph node transfer in chronic lymphedema in a canine model.12 Stable below-knee lymphedema was established in dogs by irradiation and circumferential skin excision at the knee, followed by popliteal lymphadenectomy. A free groin lymph node flap with abundant perinodal tissue was transferred to the popliteal fossa and inset to bridge the zone of dense fibrosis between the proximal and distal normal tissues. A statistically significant reduction in excess limb circumference was seen at 3 months; however, none of the limbs returned to normal size at the 6-month follow-up. Postoperative lymphangiography demonstrated spontaneous recanalization of the lymphatic channels with drainage across the obstructed zone, but no comment was made on visualization of the transferred lymph nodes. Postoperative lymphoscintigraphy showed uptake of the radiotracer by the transferred lymph node and liver, but it was not quantified. Tobbia et al. compared the effect of vascularized versus avascular lymph node transfer in an ovine model.13 Lymphatic function 8 to 12 weeks after transfer was significantly higher in the vascularized group. Similarly, postoperative edema was less in the vascularized versus avascular lymph node transfer group; however, it failed to register significance. Vascular endothelial growth factor (VEGF)-C is recognized as the principal regulator of lymphangiogenesis.19 Administration of exogenous VEGF-C has been shown to improve functional integration of transferred avascular and vascularized lymph nodes in animal models.14,15 However, some concerns have been raised regarding the use of VEGF-C in cancer patients, as it may enhance tumor growth and metastasis.20,21 Other experiments have shown that expression of endogenous VEGF-C is markedly raised at the sites of lymphangiogenesis and that it can be further enhanced by induction of a sterile inflammatory response after lymph node transfer.16,17,22 In summary, there is good evidence to suggest that avascular lymph node fragments autotransplanted into suitable recipient sites will regenerate into lymphoid tissues. Maintaining vascularization of the transferred lymph nodes ensures their survival and is essential when a lymph node–bearing block of tissue is transferred. There is also good experimental evidence to suggest that the
transferred lymph nodes are able to integrate with the recipient site’s lymphatic circulation soon after its disruption. However, two fundamental questions remain unanswered: 1. What is the efficacy of lymph drainage across the transferred lymphatic tissue? This question could only be addressed by experiments in which a sustained lymph stasis was generated and then the effect of transfer on edema was compared with a control group. The experiments by Fu et al. on rabbits’ ears and by Chen et al. on dogs’ legs improved the edema but failed to completely resolve it.8,12 In the experiment by Tobbia et al. on sheep, a sustained edema was not generated, and in all groups the edema improved over the course of the study, although this was quicker in the vascularized lymph node transfer group.13 2. Will the transferred lymph nodes integrate with the recipient site’s lymphatics that are affected by chronic lymphedema? The only chronic lymphedema model was the canine model used by Chen et al. in which a large lymphatic-rich flap was used to bridge the entire zone of lymphatic obstruction.12 However, in clinical cases of chronic lymphedema, the zone of lymphatic abnormality has often extended distally much beyond the initial lymphadenectomy zone, which cannot be traversed by the lymph node flap.23 This reduces the availability of “open” lymphatic channels as pointed out by Shesol et al.11
FUNCTIONAL MECHANISMS Two main hypotheses have been proposed to explain the potential functional mechanism of vascularized lymph node transfer in chronic lymphedema (Fig. 1). One proposed mechanism is that the lymph node flap is naturally rich with lymphatic collectors and simply acts as a lymphatic wick to bridge the zone of obstruction. The concept of lymphatic wick is not new in the history of reconstructive lymphatic surgery. Surgeons have used silk threads, fascial strips, omentum, or skin flaps to treat lymphedema by this mechanism.24 For a lymphatic flap to function as an effective wick, two requirements must be met. First, the flap must bridge the entire zone of obstruction, with functional lymphatics present proximally and distally at the recipient site. Clinically, this is possible when the vascularized lymph
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Plastic and Reconstructive Surgery • March 2016
Fig. 1. Schematic diagram showing the two theories on the functional mechanism of vascularized lymph node transfer. In both theories, spontaneous anastomosis between the afferent lymphatics of the donor site and the transferred lymph nodes is required. In the lymphatic wick theory (left), spontaneous anastomosis between the lymph nodes and the efferent lymphatics of the recipient site is required to bridge the lymphatic gap. In the lymphatic pump theory (right), the intrinsic lymphovenous shunts within the transferred lymph nodes is responsible for redirecting the lymph load to the venous circulation.
node transfer is performed immediately after lymph node dissection or at the very early stages of lymphedema. Second, spontaneous lympholymphatic anastomosis must form between the donor and recipient lymphatics at the proximal and distal stump that can effectively drain the lymphatic load of the limb. It has been suggested that the transferred lymph nodes may act as an endogenous source of VEGF-C that augments lymphangiogenesis after transfer25; however, solid scientific evidence to support this hypothesis is lacking. As mentioned above, although reintegration into the recipient lymphatics has been shown, the efficiency of these connections is yet to be examined. The other proposed mechanism is that the lymph node–bearing flap transferred to the distal extremity acts as a lymphatic pump by absorbing the interstitial fluid that has gravitated down the limb and shifting it into the systemic circulation by means of the intrinsic lymphovenous shunt within the nodes. It has been shown that approximately 50 to 66 percent of the lymph is resorbed back to the systemic circulation within the lymph nodes.26 In a study by Cheng et al., when indocyanine green was injected into the edges of the lymph node flaps,
it was quickly seen in the donor vein and then in the recipient vein.27 However, when it was injected into the subcutaneous fat of the deep inferior epigastric artery perforator flap, it failed to distribute. They concluded that the indocyanine green was absorbed by the transferred lymph nodes within the flap and drained into the donor vein through its native lymphovenous shunt. This observation, although interesting, is not conclusive. First, their findings can be alternatively explained by the known rich blood supply of the nodes and perinodal tissues compared with the relatively low blood supply of the subcutaneous fat. Absorption of the indocyanine green by the blood capillaries of the donor tissue could have produced the same result. Second, the manner by which the lymph gains entry into the node is not very clear in this proposed mechanism. It is known that the afferent collectors are not absorptive vessels. Lymph absorption only occurs at the level of capillary lymphatics and to a limited extent by the precollectors.28 In his microlymphangiographic studies on rabbit ear models, Oden showed that newly formed capillary lymphatics sprouted out from the severed ends of collectors and eventually joined with the other
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Volume 137, Number 3 • Vascularized Lymph Node Transfer collectors in the vicinity.29 However, this cannot explain absorption of lymph into the node immediately after surgery. Recently, Aschen et al., in an innovative experiment on an acute lymphedema model in transgenic mice, were able to show massive infiltration of recipient lymphatics into the transferred lymph nodes, spontaneous anastomosis between the recipient and donor lymphatics, and close proximity of the lymphatics to the high endothelial venules of the lymph nodes.16 It will be interesting to see whether these results can be reproduced in a chronic lymphedema model.
CLINICAL EXPERIENCE WITH VASCULARIZED LYMPH NODE TRANSFER Table 23,25,30–34 summarizes study methodologies of the published clinical series on vascularized lymph node transfer. Although improvement in lymphedema symptoms has been reported in most studies, the level of evidence to advocate this procedure in the treatment of chronic lymphedema remains low because of the small number of cases and problems in their methodologies, as follows: 1. Patient selection: Lymphedema is a chronic progressive condition that is characterized by chronic lymph stasis, which eventually leads to fibrosis and adipose hypertrophy of the subcutaneous tissues.35,36 Successful restoration of the normal limb volume by any of the available physiologic procedures directly depends on the proportional degree of the latter irreversible changes. The published case series included a heterogeneous group of patients with a wide range of duration and severity of lymphedema. In the future, the use of advanced imaging modalities including magnetic resonance imaging and indocyanine green lymphography can improve preoperative staging and patient selection.37–39 2. Conservative therapy: It is possible that patients who have chosen surgery for their lymphedema are more motivated in their treatment. Such patients may also be more likely to be compliant with their prescribed postoperative physiotherapy regimen, which can confound interpretation of the results. Selecting patients who are on a stable complete decongestive therapy regimen preoperatively and postoperatively can potentially eliminate this confounding factor. Patients can then be gradually weaned off complete decongestive therapy depending on their response.
3. Outcome measures: a. Subjective assessment of lymphedema symptoms reported by patients is unreliable; to quote Puckett: “These unfortunate and usually neglected (lymphedema) patients are delighted to find an interested, caring, and enthusiastic physician, and they will reliably ‘do better’ for us regardless of their status of objective improvement.”40 b. Circumference measurements used by the published series notoriously lack reliability in monitoring lymphedema volume.41 Volume displacement remains the gold standard but is inconvenient for both patients and researchers. Alternatively, perimetric measures with 5- to 10-cm increments can be put in the truncated cone formula to calculate the limb volume, which closely correlates with the volume displacement method and has been shown to have excellent interobserver and intraobserver reproducibility.42,43 c. Quantitative assessment of lymphatic function with lymphoscintigraphy has been regularly used in experimental studies of lymph node transfer. In the published clinical series, although lymphoscintigraphy was often performed, a systematic quantitative analysis was missing. d. Other methods such as bioelectrical impedance analysis,44 tissue tonometry,45 and magnetic resonance imaging46 can be used to more objectively monitor the therapeutic response. 4. Follow-up: Clinical lymphedema occurs when the lymph load of an extremity exceeds its lymph transport capacity. Therefore, even complete postoperative resolution of edema—unless the transport capacity is fully restored—does not mean that the procedure has cured the condition, but at best has returned lymphedema to its latent phase. With time, the remaining collectors overloaded with lymph will decompensate and clinical edema will recur.24,47 Therefore, long-term follow-up is required to assess the efficacy of vascularized lymph node transfer in the treatment of chronic lymphedema. 5. Study design: Most published studies to date are uncontrolled case series with small numbers. High-quality randomized controlled studies are needed to conclusively endorse or repudiate this procedure.
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10 Cheng et al.. 201333
LS, lymphoscintigraphy; ISL, International Society of Lymphology. *International Society of Lymphology. The diagnosis and treatment of peripheral lymphedema: 2009 Consensus Document of the International Society of Lymphology. Lymphology 2009:42:51–60.
III Prospective controlled 39.1 ± 15.7 mo
9 Saaristo et al., 201225
Three times per week for 1 mo then twice weekly for 2 mo Nil
Subjective patient survey, rate of cellulitis, limb circumference
IV Prospective 8–24 mo
IV
Subjective patient survey, rate of cellulitis, limb Circumference, Limb circumference, quantitative LS 7 Cheng et al., 201232
Not routinely used
36–120 mo duration, stage II and III (ISL)*, treatment resistant 6–120 mo duration, excluding longstanding severe edema 12–84 mo duration, stage II (ISL)*
21 Gharb et al., 201131
No comment Early stage II (ISL)*, resistant to at least 6 mo of conservative therapy
13 Lin et al., 200930
No comment
Prospective
IV Retrospective
Standard group: 26–120 mo (46 mo) Hilar group: 38–50 mo (40 mo) 2–22 mo (8.7 mo)
IV Prospective 6–96 mo (56.3)
IV Retrospective 5–11 yr (8.3 yr)
Rate of cellulitis, limb circumference, qualitative LS Subjective patient survey, limb circumference, qualitative LS Subjective patient survey, rate of cellulitis, limb circumference Daily for 3 mo then biweekly for 3 mo
3 mo–15 yr duration, treatment resistant, excluding elephantiasis 4–84 mo duration 24 Becker et al., 20063
Follow-Up (Mean) Outcome Measures Postoperative Physiotherapy Lymphedema Severity No. of Patients Study
Table 2. Summary of Study Methodologies of Published Clinical Series on Vascularized Lymph Node Transfer
Study Design
Level of Evidence
Plastic and Reconstructive Surgery • March 2016 RISK OF IATROGENIC LYMPHEDEMA The most frequently used donor site in vascularized lymph node transfer is the groin, where the superolateral superficial inguinal lymph nodes are harvested on the superficial circumflex iliac artery or the superficial inferior epigastric artery. Its familiar anatomy, a hidden cosmetic scar, and its capacity to be raised in continuity with abdominal flaps for autologous breast reconstruction have made the groin the most suitable donor site for breast cancer–related secondary lymphedema. Although the groin flap has been used for many years with no reports of iatrogenic lymphedema in the donor limb, some concerns have been raised recently with regard to the safety of this flap in patients with lymphedema.48–50 Two factors can possibly explain the emergence of these concerning reports. First, lymphedema is a notoriously underdiagnosed condition.51 The increased awareness of lymphedema as a complication in both the patient and the treating surgeon after vascularized lymph node transfer is likely to facilitate its diagnosis. In contrast, unless they are proactively sought, the signs and symptoms of lymphedema are more likely to be missed in a grateful patient following a life- or limb-saving groin flap procedure. Second, patients with secondary lymphedema may be constitutionally predisposed to this condition.52–55 Although the reduction in lymphatic drainage of the donor limb may be well tolerated in a patient with normal lymphatic function, it may lead to lymphedema in patients with constitutionally reduced lymph transport capacity. Therefore, it is of utmost importance to preserve the lymphatic function of the donor site in these patients. The nodes of interest in the groin lymph node flap are the superolateral group of the superficial inguinal lymph nodes that are located along the superficial circumflex iliac vein (Fig. 2). In contrast, cadaveric, direct lymphangiography, and single-photon emission computed tomographic studies have shown that the primary superficial nodes draining the lower limb are located just below the saphenofemoral junction (located at the groin crease) and medial to the femoral artery.56–58 Therefore, to preserve the lymphatic function of the lower limb when harvesting the groin lymph node flap, it is crucial to dissect superficial to the deep fascia and limit the medial and inferior borders of the dissection to the femoral artery and the groin crease, respectively. In addition to these anatomical landmarks, Dayan et al. suggested reverse lymphatic mapping using a combination of indocyanine green lymphography
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Volume 137, Number 3 • Vascularized Lymph Node Transfer nodes were the primary nodes draining the local collectors of the thigh; the latter originate from the watershed area of the posterior thigh.61,62 Therefore, even careful selection of these nodes may marginally affect the lymphatic function of the lower limb, which theoretically in the long term may lead to clinical lymphedema in a small percentage of patients. Alternative donor sites including submental, axillary, and supraclavicular flaps are mainly used in cancer-related secondary lymphedema of the lower limbs, where the groin lymph nodes are not available because of surgery, radiation therapy, and other factors. The development of contralateral axillary lymph node metastases following the treatment of unilateral breast cancer in 3.6 to 6 percent of cases discourages use of axillary lymph nodes in patients with breast cancer.9 The unsightly scars and the possibility of nerve injuries disadvantage the neck donor sites. Anatomical studies are currently underway to examine the details of these and potential new donor lymphatic tissues. Fig. 2. Topographically, the superficial inguinal lymph nodes are divided into five zones by a horizontal line and a vertical line intersecting at the saphenous bulb (Daseler EH, Anson BJ, Reimann AF. Radical excision of the inguinal and iliac lymph glands; a study based upon 450 anatomical dissections and upon supportive clinical observations. Surg Gynecol Obstet. 1948;87:679–694.): the superomedial group (SM) associated with the superficial epigastric vein (1), the inferomedial group (IM) associated with the superficial external pudendal veins (2), the inferolateral group (IL) associated with the great saphenous vein (3) and the lateral accessory saphenous vein (4), the superolateral group located along the superficial circumflex iliac vein (5), and the central group (C) located over the saphenous bulb. The nodes of interest in vascularized lymph node transfer with a groin donor site are the superolateral (SL) group. When harvesting the groin lymph node flap for vascularized lymph node transfer, the dissection should stay lateral to the femoral artery (shown in red) and proximal to the groin crease. The danger zone (shaded in orange) must be avoided in order to preserve the lymphatic function of the lower limb.
and lymphoscintigraphy to more precisely guide flap harvest in individual patients.59 It should be noted that although the superolateral group of the superficial inguinal lymph nodes are mainly involved with the drainage of the lower abdomen, lower back, and the upper gluteal region, this is not exclusive. Caplan studied the lymphatic drainage of the great toe in 50 human fetuses and found drainage to these nodes in nine cases.60 In another study in patents with malignant melanoma of the lower limb, the sentinel node was located in the superolateral zone in 5 percent of the cases.58 Direct injection studies in adult human cadavers by the current authors revealed that the superolateral
SUMMARY Neither of the proposed functional mechanisms of vascularized lymph node transfer is strongly supported by the available experimental evidence, and more basic research is needed on chronic lymphedema models. The initial results of vascularized lymph node transfer in the treatment of chronic lymphedema have been promising thus far. However, the level of evidence to support this procedure as the standard therapy for chronic lymphedema remains low, and longterm well-designed studies are required. Further anatomical studies to explore potential new donor sites are needed, and it is crucial that iatrogenic chronic morbidities are not caused in the interim. Saam S. Tourani, M.D. Department of Anatomy and Neuroscience University of Melbourne Room E533 Medical Building Grattan Street Parkville, Victoria 3010, Australia [email protected]
ACKNOWLEDGMENTS
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