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Complications of Autologous Lymph-node Transplantation for Limb Lymphoedema

  • S. Vignes
    Correspondence
    Corresponding author. S. Vignes, Department of Lymphology, Hôpital Cognacq-Jay, 15, rue Eugène Millon, 75015 Paris, France. Tel.: +33 1 45 30 81 35; fax: +33 1 45 30 81 34.
    Affiliations
    Department of Lymphology, Centre National de Référence des Maladies Vasculaires Rares (lymphœdèmes primaires), Hôpital Cognacq-Jay, 15, rue Eugène Millon, 75015 Paris, France
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  • M. Blanchard
    Affiliations
    Department of Lymphology, Centre National de Référence des Maladies Vasculaires Rares (lymphœdèmes primaires), Hôpital Cognacq-Jay, 15, rue Eugène Millon, 75015 Paris, France
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  • A. Yannoutsos
    Affiliations
    Department of Lymphology, Centre National de Référence des Maladies Vasculaires Rares (lymphœdèmes primaires), Hôpital Cognacq-Jay, 15, rue Eugène Millon, 75015 Paris, France
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  • M. Arrault
    Affiliations
    Department of Lymphology, Centre National de Référence des Maladies Vasculaires Rares (lymphœdèmes primaires), Hôpital Cognacq-Jay, 15, rue Eugène Millon, 75015 Paris, France
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Open ArchivePublished:January 09, 2013DOI:https://doi.org/10.1016/j.ejvs.2012.11.026

      Objective

      This study aims to assess potential complications of autologous lymph-node transplantation (ALNT) to treat limb lymphoedema.

      Design

      Prospective, observational study.

      Method

      All limb-lymphoedema patients, followed up in a single lymphology department, who decided to undergo ALNT (January 2004–June 2012) independently of our medical team, were included.

      Results

      Among the 26 patients (22 females, four males) included, 14 had secondary upper-limb lymphoedema after breast-cancer treatment and seven had secondary and five primary lower-limb lymphoedema. Median (interquartile range, IQR) ages at primary lower-limb lymphoedema and secondary lymphoedema onset were 18.5 (13–30) and 47.4 (35–58) years, respectively. Median body mass index (BMI) was 25.9 (22.9–29.3) kg m−2. For all patients, median pre-surgery lymphoedema duration was 37 (24–90) months. Thirty-four ALNs were transplanted into the 26 patients, combined with liposuction in four lower-limb-lymphoedema patients. Ten (38%) patients developed 15 complications: six, chronic lymphoedema (four upper limb, two lower limb), defined as ≥2-cm difference versus the contralateral side, in the limb on the donor lymph-node-site territory, persisting for a median of 40 months post-ALNT; four, post-surgical lymphocoeles; one testicular hydrocoele requiring surgery; and four with persistent donor-site pain. Median (IQR) pre- and post-surgical lymphoedema volumes, calculated using the formula for a truncated cone, were, respectively, 1023 (633–1375) ml (median: 3 (1–6) months) and 1058 (666–1506) ml (median: 40 (14–72) months; P = 0.73).

      Conclusion

      ALNT may engender severe, chronic complications, particularly persistent iatrogenic lymphoedema. Further investigations are required to evaluate and clearly determine its indications.

      Keywords

      This report concerns the complications arising after autologous lymph-node transplantation to treat primary or secondary upper- or lower-limb lymphoedema, including persistent iatrogenic lymphoedema of the limb corresponding to the donor-node site. Patients must be made aware of the potential risk of grafting before undergoing surgery.
      Lymphoedema is a chronic and often debilitating disorder caused by lymphatic insufficiency. It can be either primary or secondary, mainly after cancer treatment including surgery and/or radiotherapy. Lymphoedema management is based upon complete decongestive physiotherapy and is divided into two phases: the first, to reduce lymphoedema volume, and the second, to maintain the reduced volume. It includes multilayer low-stretch bandages to diminish lymphoedema volume, exercise and meticulous skin care followed by the wearing of elastic garments to stabilise the volume.
      • Harris S.R.
      • Hugi M.R.
      • Olivotto I.A.
      • Levine M.
      Steering Committee for Clinical Practice Guidelines for the Care and Treatment of Breast Cancer
      Clinical practice guidelines for the care and treatment of breast cancer: 11. Lymphedema.
      Surgical treatment of lymphoedema has been advocated as an alternative or adjunctive technique with the aim of ‘curing’ the disease. Several categories of surgical procedures have been proposed to treat lymphoedema, including excisional procedures (after intensive complete physiotherapy and cutaneous resection to remove excess limb flaps or lymphoedematous genital skin), liposuction, lymphatic reconstructions (lymphovenous anastomosis and lymphatic channel graft) and tissue-transfer procedures (autologous lymph-node transplantation (ALNT) and autologous stem-cell transplantation).
      • Cormier J.N.
      • Rourke L.
      • Crosby M.
      • Chang D.
      • Armer J.
      The surgical treatment of lymphedema: a systematic review of the contemporary literature (2004–2010).
      Complications of the surgery are rarely mentioned in articles. Among the different types of surgery, ALNT, essentially proposed to treat patients with cancer-related or primary lymphoedema, can be responsible for complications due to lymph-node excision.
      • Becker C.
      • Assouad J.
      • Riquet M.
      • Hidden G.
      Postmastectomy lymphedema: long-term results following microsurgical lymph node transplantation.
      • Becker C.
      • Pham D.N.
      • Assouad J.
      • Badia A.
      • Foucault C.
      • Riquet M.
      Postmastectomy neuropathic pain: results of microsurgical lymph nodes transplantation.
      • Becker C.
      • Vasile J.V.
      • Levine J.L.
      • Batista B.N.
      • Studinger R.M.
      • Chen C.M.
      • et al.
      Microlymphatic surgery for the treatment of iatrogenic lymphedema.
      • Becker C.
      • Arrive L.
      • Saaristo A.
      • Germain M.
      • Fanzio P.
      • Batista B.N.
      • et al.
      Surgical treatment of congenital lymphedema.
      In this study, we analysed the complications arising in patients whose limb lymphoedema was treated with ALNT.

      Patients and Methods

      Subjects

      All patients with primary or secondary limb lymphoedema, who had undergone ALNT between January 2005 and June 2012 and were included in this observational study, were followed up prospectively for their initial lymphoedema and the evaluation of the limb corresponding to the donor site in our centre specialised in lymphoedema management; they continue to be followed up prospectively. Our centre manages lymphoedema diagnosis, its medical treatment, that is, intensive decongestive physiotherapy, educational and counselling measures, adapted physical activities and long-term follow-up during the maintenance phase but not surgery. All patients made the decision to undergo ALNT with the hope of ‘curing’ their disease and thereby avoiding the constraining long-term compression therapy. Our medical team was not implicated in this decision.
      Iatrogenic lymphoedema was clinically diagnosed as increased limb volume with ≥2-cm difference compared to the contralateral non-lymphoedematous limb, as used for upper-limb lymphoedema after breast-cancer treatment.
      • Armer J.M.
      • Stewart B.R.
      A comparison of four diagnostic criteria for lymphoedema in a post-breast cancer population.
      For the lower limb, the clinical diagnosis was confirmed by the thickening of the skin of the dorsal side of the foot (Kaposi–Stemmer sign).

      Data collected

      The following information was recorded: patient characteristics, body mass index (BMI = BW (kg)/H2 (m2), where BW is body weight and H height) at the time of the first examination and lymphoedema characteristics (date of onset and duration, lymphoedema volume at inclusion, primary or secondary, past cellulitis (erysipelas)). Breast-cancer treatment included mastectomy (n = 7) or tumourectomy (n = 7) with axillary lymph-node dissection and radiotherapy (n = 14) and chemotherapy (n = 12). Secondary lower-limb lymphoedema was associated with cervical cancer treatment, including radical hysterectomy with pelvic lymphadenectomy and brachytherapy (n = 4), endometrial cancer (n = 1) and testicular cancer or inguinal hamartoma, one each.
      Specific lymphoedema treatments were also recorded (multilayer low-stretch bandage, manual lymph drainage and elastic garment).

      Lymphoedema volume

      The volume of the lymphoedema was calculated for each 5-cm segment using the formula for a truncated cone: H × (C2 + Cc + c2)/12π, where H is height and C and c the circumferences of the top and base of the cone, respectively.
      • Sitzia J.
      Volume measurement in lymphoedema treatment: examination of formulae.
      The ‘0’ starting point for the measurement was the elbow fold for the upper limb and the lower edge of the patella for the lower limb. Limb circumferences were measured every 5 cm: for the upper limb, 20 cm from 0 to the wrist and 15 cm from 0 to the shoulder and for lower limb, 30–35 cm from 0 to the ankle and 25–30 cm from 0 to the hip.
      This method has demonstrated excellent inter- and intra-observer reproducibilities for lower and upper limbs, when compared to water displacement, which remains the gold standard.
      • Galland C.
      • Auvert J.F.
      • Flahault A.
      • Vayssairat M.
      Why and how post-mastectomy edema should be quantified in patients with breast cancer.
      • Kaulesar Sukul D.M.
      • den Hoed P.T.
      • Johannes E.J.
      • 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.
      Lymphoedema volume was defined as the difference between the lymphoedematous limb volume and that of the healthy limb before and after ALNT.

      ALNT

      The technical procedure has been described previously.
      • Becker C.
      • Vasile J.V.
      • Levine J.L.
      • Batista B.N.
      • Studinger R.M.
      • Chen C.M.
      • et al.
      Microlymphatic surgery for the treatment of iatrogenic lymphedema.
      • Becker C.
      • Arrive L.
      • Saaristo A.
      • Germain M.
      • Fanzio P.
      • Batista B.N.
      • et al.
      Surgical treatment of congenital lymphedema.
      Briefly, the axillary or inguinal donor-site area was meticulously dissected. Lymph nodes were harvested with an abundant amount of surrounding fat and were then transplanted into the axillary or inguinal receiving site of the lymphoedematous limb. Artery and vein were anastomosed with the previously prepared vessels, using microsurgical techniques. Both axillary and inguinal approaches were closed on suction drainage.

      Statistical analyses

      Results are expressed as medians (interquartile range, IQR) or n (%). Paired Student's t-test was used for comparisons. P < 0.05 defined significance.

      Results

      Twenty-six patients (22 females, four males) were included: 14 with secondary upper-limb lymphoedema, seven with secondary lower-limb and five with primary lower-limb lymphoedema. At the first examination, median BMI was 25.9 (IQR: 22.9–29.3) kg m−2. Median age at onset of primary lower-limb lymphoedema and secondary lymphoedema were 18.5 (IQR: 13–30) and 47.4 (IQR: 35–58) years, respectively. For all the patients, median lymphoedema duration before surgery was 37 (IQR: 24–90) months.
      Thirty-four ALNs were engrafted into the 26 patients and combined with liposuction for four patients with lower-limb lymphoedema (three secondary, one primary).

      Complications

      Table 1 lists the 15 complications that occurred post transplantation in 10 (38%) patients, including persistent lymphoedema that appeared during the first year in the limb corresponding to the donor lymph-node site (n = 6: four upper limb, two lower limb) and persisted for a median of 40 months post ALNT (see Fig. 1), lymphocoele (n = 4, requiring one or more punctures), testicular hydrocoele (n = 1, requiring surgery) and persistent donor-site pain (n = 4). One patient developed postoperative staphylococcal spondylodiscitis, considered a nosocomial infection, successfully treated with prolonged antibiotic therapy.
      Table 1Characteristics of lymphoedema and complications after ALNT according to order and limb.
      PatientSex, ageLymphoedemaPregraft duration (mo)Donor-site, sideComplications
      Aetiology, side
      Secondary
      Upper limbBreast cancer
       1F, 52Left36Inguinal, rightLymphoedema right lower limb, donor-site pain
       2F, 42Right80Inguinal, left
       3F, 64Left96Inguinal, right
       4F, 68Right125Inguinal, right & left
       5F, 63Right33Inguinal, leftDonor-site pain, lymphocele
       6F, 80Left86Inguinal, right
       7F, 69Right28Inguinal, leftDonor-site pain, lymphocele
       8F, 68Left7Inguinal, right
       9F, 48Left17Inguinal, right & left
       10F, 67Right212Inguinal, rightLymphocele
       11F, 36Left39Inguinal, rightLymphoedema right lower limb
       12F, 48Left105Inguinal, right
       13F, 59Left28Inguinal, right
       14F, 49Left23Inguinal, right
      Lower limb
       15F, 46Cervical cancer, right29Axillary, left
       16F, 46Cervical cancer, left16Axillary, right & left; inguinal, right
       17F, 33Endometrial cancer, left15Axillary, leftLymphocele
       18F, 31Cervical cancer, right67Axillary, right & left
       19M, 35Inguinal hamartoma, left49Axillary, left; inguinal, rightLymphoedema left upper limb, hydrocoele
       20M, 42Testicular cancer, right182Axillary, leftLymphoedema, left upper limb, donor-site pain
       21F, 63Cervical cancer, left31Axillary left
      Primary lower limb
       22M, 47Right178Axillary, right & left
       23F, 10Right37Axillary, left
       24F, 20Left20Inguinal, right
       25F, 30Right2Axillary, rightLymphoedema right upper limb
       26M, 21Right91Axillary, right; inguinal leftLymphoedema right upper limb
      Figure thumbnail gr1
      Figure 1Patient 25, a 30-year-old woman, developed iatrogenic lymphoedema of the right hand after ALNT from the right axillary donor site to the right inguinal site to treat primary lower-limb lymphoedema.

      Lymphoedema volume and its management

      Median (IQR) lymphoedema volumes were 1023 (633–1375) ml before ALNT (median: 3 (1–6) months) and 1058 (666–1506) ml thereafter (median: 40 (14–72) months; P = 0.73). After a median 40 months of follow-up post ALNT, treatment of the initial lymphoedema included self-applied bandages (after learning from a specialised physiotherapist) for 24 (92%), manual lymph drainage for 25 (96%) and an elastic garment for all patients. For the upper limb, the elastic garment was always 20–36 mmHg, and, for the lower limb, one (n = 2) or two superposed (n = 6), or superposed 20–36 mm Hg and >36 mm Hg (n = 4). Iatrogenic lymphoedema was treated like the initial lymphoedema, with low-stretch bandages, an elastic garment and, sometimes, manual lymph drainage.

      Discussion

      This is the first report devoted to complications that arose after ALNT (n = 15) to treat primary or secondary limb lymphoedema in 10 patients. Some of them were transitory, such as lymphocoele and hydrocoele, which were cured by puncture or surgery. Others that persisted were irreversible, such as iatrogenic lymphoedema on the donor-site side, and chronic pain localised in the region of the superficial femoral nerve, as previously described in 13 patients.
      • Viitanen T.P.
      • Mäki M.T.
      • Seppänen M.P.
      • Suominen E.A.
      • Saaristo A.M.
      Donor site lymphatic function after microvascular lymph node transfer.
      Iatrogenic lymphoedema becomes a chronic disease with its own complications, for example, worsening or cellulitis. Iatrogenic secondary lymphoedema required a specific therapeutic regimen with low-stretch bandages, compression therapy and, sometimes, manual lymph drainage. In previous retrospective studies on humans, ALNT seemed to attenuate upper-limb cancer-related lymphoedema resistant to complete decongestive physiotherapy or post-mastectomy chronic pain in women treated for breast cancer.
      • Becker C.
      • Assouad J.
      • Riquet M.
      • Hidden G.
      Postmastectomy lymphedema: long-term results following microsurgical lymph node transplantation.
      • Becker C.
      • Pham D.N.
      • Assouad J.
      • Badia A.
      • Foucault C.
      • Riquet M.
      Postmastectomy neuropathic pain: results of microsurgical lymph nodes transplantation.
      In those studies, lymphoedema volume was not objectively quantified (volumetry) and no complications were reported. In addition, resistance to physiotherapy is not a term clearly defined in the literature. It should be noted that our patients decided to undergo ALNT to treat their lymphoedema, with the hope of curing it and stopping compression therapy, without informing or consulting our medical team.
      Only 15–20% of women develop lymphoedema after breast-cancer treatment including axillary lymph-node dissection and only 3.5–7% after sentinel node biopsy.
      • Tsai R.J.
      • Dennis L.K.
      • Lynch C.F.
      • Snetselaar L.G.
      • Zamba G.K.
      • Scott-Conner C.
      The risk of developing arm lymphedema among breast cancer survivors: a meta-analysis of treatment factors.
      • Wilke L.G.
      • McCall L.M.
      • Posther K.E.
      • Whitworth P.W.
      • Reintgen D.S.
      • Leitch A.M.
      • et al.
      Surgical complications associated with sentinel lymph node biopsy: results from a prospective international cooperative group trial.
      • Langer I.
      • Guller U.
      • Berclaz G.
      • Koechli O.R.
      • Schaer G.
      • Fehr M.K.
      • et al.
      Morbidity of sentinel lymph node biopsy (SLN) alone versus SLN and completion axillary lymph node dissection after breast cancer surgery: a prospective Swiss multicenter study on 659 patients.
      • McLaughlin S.A.
      • Wright M.J.
      • Morris K.T.
      • Sampson M.R.
      • Brockway J.P.
      • Hurley K.E.
      • et al.
      Prevalence of lymphedema in women with breast cancer 5 years after sentinel lymph node biopsy or axillary dissection: patient perceptions and precautionary behaviors.
      Major risk factors for lymphoedema include the number of axillary lymph nodes resected, external radiotherapy and obesity.
      • Tsai R.J.
      • Dennis L.K.
      • Lynch C.F.
      • Snetselaar L.G.
      • Zamba G.K.
      • Scott-Conner C.
      The risk of developing arm lymphedema among breast cancer survivors: a meta-analysis of treatment factors.
      • Wilke L.G.
      • McCall L.M.
      • Posther K.E.
      • Whitworth P.W.
      • Reintgen D.S.
      • Leitch A.M.
      • et al.
      Surgical complications associated with sentinel lymph node biopsy: results from a prospective international cooperative group trial.
      As suggested by Newman et al., patients suffering from lymphoedema after cancer therapy probably have predisposing factors, partially genetic, which might contribute to increasing the risk of lymphoedema subsequent to treatment inducing lymphatic lesions.
      • Newman B.
      • Lose F.
      • Kedda M.A.
      • Francois M.
      • Ferguson K.
      • Janda M.
      • et al.
      Possible genetic predisposition to lymphedema after breast cancer.
      Moreover, lymphatic function explorations in the contralateral limbs of patients with primary lymphoedema showed abnormalities indicating impaired lymphatic function.
      • Burnand K.M.
      • Glass D.M.
      • Mortimer P.S.
      • Peters A.M.
      Lymphatic dysfunction in the apparently clinically normal contralateral limbs of patients with unilateral lower limb swelling.
      Those findings might suggest more diffuse lymphatic insufficiency not localised only to the lymphoedematous limb territory. Moreover, near-infrared fluorescent imaging of lymphatic function in the contralateral normal limb of patients with secondary upper-limb lymphoedema showed lymphatic abnormalities in the affected and non-lymphoedematous limbs.
      • Aldrich M.B.
      • Guilliod R.
      • Fife C.E.
      • Maus E.A.
      • Smith L.
      • Rasmussen J.C.
      • et al.
      Lymphatic abnormalities in the normal contralateral arms of subjects with breast cancer-related lymphedema as assessed by near-infrared fluorescent imaging.
      Considering more extensive and diffuse lymphatic insufficiency and genetic predisposition, ALNT might create a lymphatic function imbalance in these patients, leading to lymphoedema onset in the donor-site side.
      The absence of lymphoedema-volume regression in humans might be explained by the accumulation of adipose tissue and fibrosis, mostly chronic and irreversible, secondary to lymph stasis, as demonstrated in a mouse lymphoedema model.
      • Zampell J.C.
      • Aschen S.
      • Weitman E.S.
      • Yan A.
      • Elhadad S.
      • De Brot M.
      • et al.
      Regulation of adipogenesis by lymphatic fluid stasis: part I. Adipogenesis, fibrosis, and inflammation.
      • Aschen S.
      • Zampell J.C.
      • Elhadad S.
      • Weitman E.
      • De Brot M.
      • Mehrara B.J.
      Regulation of adipogenesis by lymphatic fluid stasis: part II. Expression of adipose differentiation genes.
      Moreover, the poor efficacy of ALNT might result from the unsustained anastomoses between the graft and existing lymphatic vessels, necessary for transplanted lymph-node function.
      • Mebius R.E.
      • Streeter P.R.
      • Brevé J.
      • Duijvestijn A.M.
      • Kraal G.
      The influence of afferent lymphatic vessel interruption on vascular addressin expression.
      Notably, in animal models (mouse and pig), damaged lymphatic networks were repaired with ALNT combined with growth factor therapy (vascular endothelial growth factor (VEGF-C, D)).
      • Tammela T.
      • Saaristo A.
      • Holopainen T.
      • Lyytikkä J.
      • Kotronen A.
      • Pitkonen M.
      • et al.
      Therapeutic differentiation and maturation of lymphatic vessels after lymph node dissection and transplantation.
      • Lähteenvuo M.
      • Honkonen K.
      • Tervala T.
      • Tammela T.
      • Suominen E.
      • Lähteenvuo J.
      • et al.
      Growth factor therapy and autologous lymph node transfer in lymphedema.
      The main strength of this study is that it was conducted in a single centre specialised in lymphology. Lymphoedema volume was measured precisely before and after ALNT with a validated and reproducible method. Patients were systematically asked about possible symptoms in the limb corresponding to the lymph-node donor site. However, our study has some limitations. The patients included in this observational study made the decision to undergo ALNT, without informing or consulting our medical team. Moreover, we included all the patients who underwent ALNT and are followed up in our Department of Lymphology, but they represent only a small percentage of the 1500 of patients who underwent this type of surgery.
      • Becker C.
      • Vasile J.V.
      • Levine J.L.
      • Batista B.N.
      • Studinger R.M.
      • Chen C.M.
      • et al.
      Microlymphatic surgery for the treatment of iatrogenic lymphedema.
      ALNT is proposed to treat primary and secondary limb lymphoedema. Patients must be alerted to the potential risk of this intervention with various potential complications that are, in part, chronic and irreversible, such as secondary lymphoedema in the donor-site limb. In our small study, ALNT failed to attenuate secondary or primary limb lymphoedema. Future prospective studies are needed to determine accurately the indications for and the long-term outcomes of ALNT in lymphoedema management.

      Funding

      None declared.

      Conflict of Interest

      None declared.

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      Linked Article

      • Angiosarcoma as a Potential Consequence of Autologous Lymph Node Transplantation for Lymphoedema
        European Journal of Vascular and Endovascular SurgeryVol. 45Issue 5
        • Preview
          With high interest have we read the article by Vignes et al., recording complications (lymphoedema, lymphocoele, hydrocoele and donor-site pain) in patients undergoing autologous lymph node transplantation (ALNT) for limb lymphoedema.1 In addition, we recently witnessed a fatal case of angiosarcoma in a 21-year-old woman. We were amazed by the unusual presentation of this aggressive tumour in such a young otherwise healthy woman, located in the right groin exactly at the site of ALNT performed 14 and 7 years before.
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