Risk Factors,pathogenesis,and Surgical Treatment For Postoperative Lower Limb Lymphedema Following Lymphadenectomy In Gynecologic Malignancies

Lymphadenectomy is the important part of the surgical treatment for gynecologic malignancies.The surgical procedure involves pelvic lymphadenectomy(PLA),inguinal lymphadenectomy and para-aortic lymphadenectomy(PALA),which increase postoperative complications.Lower Limb Lymphedema(LLL)is a frequent postoperative complication.The incidence of LLL after treatment for gynecologic cancer is reported estimates range from 0% to 70%.LLL is attributed to the impairment of lymphatic vessels due to lymphadenectomy in women with gynecologic cancers.Disruption of pelvic drainage leads to accumulation of protein-rich lymph fluid in the lower extremity,resulting in lower extremity swelling.LLL is a progressive and chronic disease.This untoward complication significantly impacts quality of life of those afflicted.It also translates into a significant financial burden for the treatment and maintenance therapy of patients afflicted with this life-long condition.However,The prevalence of LLL and its association with various risk factors,pathogenesis,treatment are not presently well understood,In particular,the potential mechanisms by which radiation therapy increases the risk of lymphedema remain essentially unknown.Therefore,this study aimed to assess the overall and cumulative incidence rates and to definitively identify risk factors using retrospective statistical analysis in patients who underwent para-aortic,pelvic or inguinal lymphadenectomy for gynecologic malignancies.We also conducted a prospective study to confirm a causal relationship between removal of circumflex iliac nodes to the distal external iliac nodes(CINDEIN)and LLL after systematic lymphadenectomy in gynecologic cancer patients.Furthermore,we sought to explore the imaging of conventional magnetic resonance imaging(MRI)and the pathological changes of lymphedematous limb,aimed to elaborate the potential mechanisms of LLL.Last,we developed a new procedure for Lymphaticovenular anastomosis(LVA)in patients with LLL with the goal of ensuring effective outcomes in all patients with LLL.PART 1 Risk Factors for Postoperative Lower Limb Lymphedema Following Lymphadenectomy in Gynecologic MalignanciesObjective This study aimed to estimate the incidence of LLL in women who underwent lymphadenectomy for gynecologic cancer and to evaluate risk factors associated with LLL.Methods We retrospectively reviewed 2153 patients with gynecologic malignancies who underwent Pelvic lymphadenectomy(PLA)with or without para-aortic lymphadenectomy(PALA)or inguinal lymphadenectomy at Guangxi Tumor Hospital between January 2012 and May 2018.The intervals between surgery and diagnosis of LLL were calculated;the prevalence and risk factors were evaluated using the Kaplan-Meier and Cox proportional hazards methods.Results we retrospectively analyzed 1489 eligible patients.Overall incidence of LLL was 17.0%(cervical cancer,18.7%;uterine corpus malignancies,15.3%;and ovarian cancer,13.1%).A significant number of lymphedema(154)can develop after 1-year postoperatively.LLL developed after a median 12 months.Using regression analysis,Age,hypertension,lymph node metastasis,stage(International Federation of Gynecology and Obstetrics),postoperative radiation therapy and chemotherapy,lymphocyst formation were found to be associated with LLL.Multivariate analysis confirmed that postoperative radiation therapy(HR,3.234;95% CI,2.441-4.285;P<0.001),and postoperative chemotherapy(HR,1.463;95% CI,1.005-2.128;P = 0.047)were independent risk factors for LLL.We used the two parameters to predict LLL,the area under curve(AUC)of the receive operating characteristic curve(ROC)was 0.682,P<0.001.The sensitivity was 86.5%,the specificity was 30.5%.The doses and the times of radiation therapy are also associated with LLL.Conclusions The overall incidence of LLL was 17.0%.Postoperative LLL incidence increased over time.A significant number of lymphedema can develop after 1-year postoperatively.The results of the present study showed a significant correlation with postoperative radiation therapy and chemotherapy with the incidence of LLL.PART 2 A Causal Relationship between Removal of Circumflex Iliac Nodes to the Distal External Iliac Nodes and LLL after Systematic Lymphadenectomy in Gynecologic Cancer PatientsObjective The aim of this study was to determine if there is a causal relationship between removal of the circumflex iliac nodes distal to the external iliac nodes(CINDEIN)and postoperative lower limb lymphedema(POLLL)after systematic lymphadenectomy in patients with gynecologic cancer,and to elucidate the incidence of CINDEIN metastasis.Methods From June 2017 to December 2018,372 patients with gynecologic cancer who had undergone abdominal complete systematic pelvic lymphadenectomy in Guang Xi Tumor Hospital were randomly divided into two groups.In group A,CINDEINs were removed,while in group B,CINDEINs were preserved.Carbon nanoparticles(CNP)were used to identify sentinel lymph nodes(SNP)in125 patients.We identified patients with POLLL.Student’s t-test or the chi-square test was used to compare the incidence of POLLL between the preserved group and nonpreserved group.Results Of 357 patients evaluated,POLLL was noted in the medical records of 41 patients(23.0%)in B group(n=178),while in A group(n=179),11 patients had POLLL.The occurrence of POLLL was signifificantly higher in the CINDEIN-dissection group than in the CINDEIN-sparing group(23% vs.6.1%,P < 0.001).The duration of LLL was longer in Group A(11.6±6.2 vs.8.1±4.5months,P=0.039).CINDEIN metastasis was observed in three(1.6%)of 186 patients.Of 125 patients with sentinel node mapping,no patient had CINDEIN detected as a sentinel node.Conclusions CINDEIN might not be regional lymph nodes in gynecologic cancer.The incidence of CINDEIN metastasis in stage Ia to IIa cervical cancer and stage I to II uterine corpus malignancies.Elimination of CINDEIN dissection can be helpful in reducing the incidence of POLLL.PART 3 Study of Pathology and Mechanisms of Postoperative Lower Limb Lymphedema Following Lymphadenectomy in Gynecologic MalignanciesObjective This study explored the imaging of conventional magnetic resonance imaging(MRI)and the pathological changes of lymphedematous limb,aimed to elaborate the potential mechanisms of POLLL after lymphadenectomy in patients with gynecologic cancer.Methods From 2018 March to 2018 September,9 patients with secondary unilateral lower limb lymphedema(they were assigned to lymphedema group)and 7 participants without POLLL(they were assigned to control group)after treatment of gynecologic malignancies were enrolled in this study.The patients in lymphedema group underwent lower extremities MRI.Full-thickness skin biopsies of lymphedematous limbs from nine patients and control samples from seven healthy controls were harvested.In order to observing the expressions of IL4、IL6、IL10、VEGF-C and TGF-β,the skin samples were assayed by HE and immunohistochemical.Results The findings of Lymphedema in conventional MRI included dermal thickening,grid change and thickening of subcutaneous tissue.Lymphedema did not cause signal change of muscle tissue.Expression of collagen in the skin of lymphedematous lower limb increased in parallel with disease stage from lymphedema stage Ⅰ to stage Ⅲ.The expression of IL4、IL10、VEGF-C and TGF-β were significantly increased in lymphedematous tissues as compared with the matched control tissues(P<0.001).All the patients had increased expression of IL-6,but the location of IL-6 were different betweet the lymphedema group and the control group.Conclusions The skin fibrosis is the important pathological process of POLLL after lymphadenectomy in patients with gynecologic cancer.IL4、IL10、VEGF-C and TGF-β is significantly increased in the lymphedematous skin,demonstrating that IL4、IL10、VEGF-C and TGF-β play an important role in the development of POLLL.PART 4 A Clinical Study of Real-time Indocyanine Green Videolymphography Navigation for Lymphaticovenular Anastomosis for POLLL Following Lymphadenectomy in Gynecologic MalignanciesObjective To assesse a new method by which we use real-time indocyanine green videolymphography navigation for LVA in the treatment of POLLL following lymphadenectomy in gynecologic cancers.Methods We chose 5 cases with secondary unilateral lower limb lymphedema after treatment of cervical cancer were enrolled in this study during September 2019 to December 2019.Three or four 2-cm-long incisions for LVA were decided using preoperative ultrasonography and preoperative lymph mapping using ICG lymphography device.A new ICG videolymphography devise and current ICG lymphography device were used in evaluating LVA procedures intraoperatively.The follow-up was conducted preoperatively and postoperatively in 1 month,3 months by assessing the symptomatic improvement and measuring lower limb volume.Results LVA was performed under local anesthesia in all 5 patients.In all anastomoses,intraoperative real-time ICG fluorescent detection of lymphatic vessels and flow through the anastomoses were accessed per ICG fluorescent features.The lower limb circumference change tendency in preoperation,1month,3 months were 40.8±5.2,39.1±5.0,38.6±5.6 cm,respectively(P>0.05).The circumference change pecentage in 1 month,3 months were 41.8%,60.2%,respectively.All patients experienced relief of symptoms and circumference reduction postoperatively.Conclusions Real-time ICG videolymphography navigation for LVA is beneficial,because the surgeon could find lymphatic vessels easily by checking dual-imaging of original and ICG fluorescent views and ensure accuracy of the LVA intraoperatively.Real-time assessment of lymphatic flow at the anastomosis could improve the accuracy of surgical procedures.LVA is more efficient in early stage lymphedema with more functional lymph vessels.