Shoubao Wang ,Jingting Chen ,Zhaohua Jiang ,Shengli Li

Department of Plastic and Reconstructive Surgery,Shanghai Ninth People’s Hospital,Shanghai Jiao Tong University School of Medicine,Shanghai 200011,China

Keywords:Lymphedema Supermicrosurgery Lymphaticovenular anastomosis

ABSTRACT The effectiveness of supermicrosurgical lymphovenous anastomosis (LVA) for lymphedema treatment remains controversial.Currently,no evidence has been summarized.This study aimed to review the published literature on supermicrosurgical LVAs in the treatment of peripheral lymphedema and to analyze the surgical outcomes.Studies from databases (PubMed/MEDLINE,Cochrane Controlled Trial Data,and Embase) were collected to determine the effectiveness of supermicrosugrical LVAs for lymphedema.A systematic review was performed using individual patient data.Fifteen studies,including 578 patients(482 female,72 male,and 24 unknown)with a mean age of 51 years,satisfied the needs of the study requirements.Supermicrosurgical LVAs for peripheral lymphedema have demonstrated substantial improvements in both objective and subjective findings in many patients.Moreover,in the long-term follow-up,the effectiveness of this treatment modality maintained a high efficacy of LVA in lymphedema cases.However,most studies provided low-quality evidence,and the conclusion is still not finalized.

1.Introduction

Over 250 million people worldwide are affected by peripheral lymphedema,a common but serious condition mostly related to cancer,characterized by accumulation of lymphatic fluid in the interstitial tissue,commonly of upper and lower extremities,and occasionally other parts of the body.1People with lymphedema experience swelling,pain,numbness,fatigue,depression,limited daily and social activities,and difficulty in wearing normal clothes because of the swollen limbs.Quality of life is greatly affected by these functional and cosmetic disabilities.2In some rare cases,chronic lymphedema can manifest in the form of malignancies,accounting for continual angiogenic stimuli,such as lymphangiosarcoma,lymphoma,and Kaposi’s sarcoma.3

In 1963,O’Brien presented a clinical report that thoroughly evaluated the use of microsurgical LVA for the treatment of obstructive lymphedema.The end-to-end(E-E)technique was employed to anastomose the proximal end of a transected lymphatic to the main trunk of a large cutaneous vein to facilitate the drainage of lymph fluid into the venous system.According to previous clinical studies,the probability of thrombosis,even deep vein thrombosis,and pulmonary embolism is high,due to the insertion of lymph into a vein and the exposure of tissues other than the endothelium to venous blood.4Although supermicrosurgical LVAs require a higher level of surgical skill than microsurgical LVAs,its advantages are non-negligible.The lymph vessel diameter is usually smaller than 0.5 mm.With the progression of microsurgical techniques,supermicrosurgery has been developed,which allows the manipulation of vessels and nerves with an external diameter of 0.1-0.5 mm.Only with supermicrosurgery can lymph vessels be securely anastomosed,and various least invasive lymphatic reconstructions become possible.

Supermicrosurgery is considered to be the latest contribution to reconstructive surgery.Although it is perceived as a new concept,it is an inevitable and natural evolution of microsurgery.5Similar to other evolutions,the fundamental principles remain unchanged,but the details of the approach are considerably different.Compared to conventional microsurgery,the application of supermicrosurgery has added something important that conventional microsurgery cannot provide.In supermicrosurgical LVAs,procedures can be minimally invasive using these small perforators,while searching and dissecting the major arteries and veins that are located deep under the skin is unnecessary,which saves time.This study aimed to review the published literature on supermicrosurgical LVAs in the treatment of peripheral lymphedema and to analyze the surgical outcomes.To our knowledge,this is the first review that includes all current studies describing supermicrosurgical LVA surgery and its effect on primary and secondary lymphedema of the upper and lower extremities.

2.Methods

2.1.Search method and study identification

This systematic review was implemented in conformity with the preferred reporting items for systematic reviews and meta-analyses(PRISMA).6Studies were identified by searching PubMed/MEDLINE,Embase,Google Scholar,and Cochrane Central.Keywords used were“supermicrosurgical”,“microsurgical”,“l(fā)ympaticovenous”,“l(fā)ympaticovenular”,“l(fā)ymphovenous”,“l(fā)ymphovenular”,“l(fā)ymphatic venous”,and“l(fā)ymphatic venular”combined with“anastomosis”.Termswere searchedin the title and ABSTRACT and mapped to medical subject headings,where applicable.No language or publication status was limited.Reduplicative articles were removed.Titles and ABSTRACT s were also screened for eligibility and then accessed in full-text articles.Other relevant articles were screened from full-text articles.The last search was performed on June 5,2021.

2.2.Inclusion and exclusion criteria

Original articles describing the application of supermicrosurgical LVAs in the treatment of peripheral lymphedema in humans were selected.Studies were excluded if they included fewer than five patients,if they were animal studies,or if the language of the article was not in English.Studies were also excluded if LVA was created to prevent lymphedema.Conventionally,the quality of evidence was determined according to the Grading of Recommendations Assessment,Development and Evaluation(GRADE)system,developed by its working group of the same name.7However,previous research indicates that most studies provide low-quality evidence.The grading system proposed by Hadamitzky et al.8was used as a secondary evidence determination standard(Table 1).This system was developed to determine the quality of studies on lymphedema surgery and facilitated the differentiation between studies with a low spectrum of evidence.Articles were excluded if they scored 0 on Item 8.Screening and inclusion of studies were performed independently by both authors S.B.W and J.T.C,while the disagreement was resolved by C.H.J.

Table 1 Quality assessment score proposed by Hadamitzky et al.8

Table 3 Synthesis of the staging method drawn up by the International Society of Lymphedema (ISL).22

Table 4 Staging of peripheral lymphedema based on clinical and lymphoscintigraphic patterns-Campisi.23

Table 5 LDB stage based on ICG lymphography findings.24

Fig.1.Flowchart according to PRISMA

2.3.Outcomes and data extraction

Study characteristics,including the study year,number of patients,average age,extremity number,follow-up,surgical technique,number of anastomoses created,patient’s BMI,and postoperative outcomes,were noted in a predefined form.

3.Results

The systematic search strategy in MEDLINE,Embase,and Cochrane Central yielded 149 papers.After screening the title and ABSTRACT ,68 studies that applied supermicrosurgical LVAs were identified.Of the 19 eligible full-text articles,15 described a brief surgical protocol and a clear outcome.The search flowchart is presented in Fig.1 along with the reasons for the exclusion of studies.The specific surgical methods used in these studies are shown in Table 2.

3.1.Lymphedema grading

Clinical stages of lymphedema consistent with Campisi were used in five of the included studies,while the grading system developed by the International Society of Lymphology was used in three studies.Legdermal backflow (LDB) and Cheng’s were both used in one study.The lymphedema staging methods used in the studies are shown in Tables 3-6.

Table 6 Grading scale for the surgical treatment of lymphedema -Cheng’s.25

3.2.Surgical technique

The intraoperative surgical technique was described in all articles.Demirtas et al.10described that supermicrosurgical LVA was used for lymphatics ＞0.3 mm in diameter,and lymphaticovenous implantation was used for smaller lymphatics.Yoshida et al.15described a supermicrosurgery technique,including intravascular stenting (IvaS),performed with and without mechanical dilation,E-E.Akita et al.16described that supermicrosurgical E-E LVA was used in the control group,and supermicrosurgical E-E LVA and valvuloplasty were used in the study group.Ito et al.17described that supermicrosurgical side-to-end(S-E)and E-E LVA were used.Koshima et al.18and Auba C et al.21both described the use of supermicrosurgical E-E LVA.Maegawa et al.19described that supermicrosurgical S-E LVA.Meanwhile,Narushima et al.20described supermicrosurgical LVA was used for 15 flow-through,1 E-E,8 end-to-side(E-S),two double E-E,two E-E/E-S,and one π-type.Koshima et al.9and Visconti G et al.14did not describe a specific LVA method in their article.

4.Discussion

The presentation and progression of lymphedema depends on the etiology,stage and extent of the edema,age,duration of the disease,anatomic region affected,and many other variables.Both conservative and surgical treatment of lymphedema aims to permanently decrease the size of the affected extremity,thereby improving skin texture and reducing or eliminating infectious episodes.26Clinical studies have shown that edema undergoes very slow reduction during conservative treatment(compression garments or bandaging,or medicine).Moreover,results of previous studies have indicated that manual lymph drainage might not contribute substantially to decreasing edema volume over the effects of compression garments or bandaging.16In 1962,Jacobson27first mentioned the creation of an anastomosis with lymphatic vessels and veins to diverge the lymphatic fluid into the venous system.LVA surgery requires anastomosis of lymphatic vessels with a diameter of 0.5-1.0 mm and veins with a diameter of 2.0-3.0 mm under general anesthesia.The application of supermicrosurgery has advantages that conventional microsurgery could not provide,which enable the anastomosis of vessels with a caliber of 0.3-0.8 mm,highly increasing the reliability of LVAs.

In this study,15 studies,including 578 patients(482 female,72 male,and 24 unknown)with a mean age of 51 years,satisfied the needs of the study requirements.Patients with extremity lymphedema at all stages were covered with different grading methods.Clinical stages of lymphedema consistent with Campisi were used in five of the included studies,while the grading system developed by the International Society of Lymphology was used in three studies.In addition,LDB and Cheng’s were both used in one study.Supermicrosurgical LVA approaches include the creation of anastomoses between lymphatic vessels and veins,between lymph nodes and veins,and between distal and proximal lymphatics.Conventional surgical methods include those such as S-E and E-E,synchronously with or without lymphaticovenous implantation and mechanical dilation.In addition,supermicrosurgical LVA,one π-type method,was indicated by Narushima et al.Currently,there is no unified protocol to guide the selection of different surgical anastomosis methods for lymphedema at different stages,and the criteria for each surgeon to choose the diagnostic grading are not uniform.Therefore,the anastomosis method that can achieve optimal surgical outcome is usually selected by the operator according to the diagnostic classification of lymphedema stages of the patient and the operator’s own familiarity with various surgical anastomosis methods.

Supermicrosurgical lymphatic anastomosis and/or lymphocyte implantation seems to be very beneficial,especially in the early stages of peripheral lymphedema,and may be considered as a treatment option for selected patients.Based on observation and analysis,the outcomes of LVAs using supermicrotechniques can be analyzed objectively and subjectively.As for objective outcomes,it has demonstrated a decrease in the diameter,as well as weight and size reduction of the affected extremities.Most patients were satisfied with the procedure and meaningful improvements in their quality of life postoperatively.Overall,supermicrosurgical LVAs have shown a high success rate and broad indications.

While supermicrosurgical LVAs are gaining popularity,there are no high-quality prospective trials evaluating these new techniques,and no studies have compared the efficiency of different surgical methods(such as E-E,S-E,and p type S-E) using the supermicrosurgical technique of LVAs for the treatment of lymphedema.After a systematic search of the eligible literature,we conclude that there is no general consensus on the staging of lymphedema and that researchers tend to apply different grading methods.Future studies should describe a detailed supermicrosurgery protocol to improve the comparison between different studies evaluating LVA.

5.Conclusion

This systematic review of the literature on the use of supermicrosurgical LVAs for lymphedema demonstrated substantial improvements in both objective and subjective findings in several patients.Moreover,in the long-term follow-up,the effectiveness of this treatment modality maintained a high efficacy of LVA in lymphedema cases.However,all the articles included in this study scored low according to the GRADE system.Most studies did not include a control group.Higher level clinical studies and evidence support are necessary to verify the effectiveness of supermicrosurgical LVAs in the treatment of lymphedema.

Ethics declarations

Ethics approval and consent to participate

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Authors’ contributions

Wang S:Writing-Reviewing and Editing,Methodology,Software.Chen J:Data curation,Writing-Original draft.Jiang Z:Visualization,Investigation.Li S:Supervision.