Lymph node transplantation in the management of post-mastectomy lymphedema: a systematic review with meta-analysis
Transplante linfonodal no manejo do linfedema pós-mastectomia: revisão sistemática com metanálise

INTRODUCTION

Breast cancer is one of the leading public health problems in Brazil¹, and, very often, it requires the surgical procedure as one of the methods for its treatment². However, one of the most frequent complications in the postoperative period of breast cancer is lymphedema, a chronic condition caused by the accumulation of fluid rich in proteins in the interstitial space^3-6, whose development can occur immediately after surgery, in rare cases, or years after the treatment^6-10.

The main risk factors for the development of lymphedema after mastectomy are lymphadenectomy and/or axillary radiation therapy, obesity, and invasive procedures performed on the limb homolateral to breast cancer^11,12. Scientific evidence has shown that mastectomy performance associated with immediate breast reconstruction can be a safe and effective method to reduce the risk of developing lymphedema¹³.

However, the occurrence of lymphedema related to breast cancer is still a reality in the routine medical clinic^13-25. To solve this occurrence, the technique of autologous transplantation of vascularized lymph nodes has been used, aiming to restore the function of the lymphatic system and interrupt the vicious cycle that causes its destruction and the progression of lymphedema^{14-19,21,23-26} However, the literature is still scarce about research that shows the success rates of using this technique in patients who developed lymphedema after mastectomy.

OBJECTIVE

This study aimed to analyze, through a systematic literature review with meta-analysis, the success rates of the use of autologous lymph node transplantation for the management of upper limb lymphedema in mastectomized patients, regarding the reduction of excessive volume in the limb affected.

METHODS

A methodology based on the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA)²² was used for systematic reviews. The most relevant studies originally published and indexed in any language until August 2019 were analyzed in the US National Library of Medicine (PubMed), Cochrane Central Register of Controlled Trials (CENTRAL), Web of Science and Scientific Electronic Library Online databases ( SciELO).

To select quality scientific evidence studies, publications were sought for meta-analysis and randomized controlled trials (RCT) in humans without restriction on publication year. The following keywords were used, in different combinations: “lymph node transfer”, “lymph node transplantation”, “lymph node graft”, “lymphedema”, “mastectomy”, “breast cancer surgery”, “postmastectomy” and “cancer.”

The inclusion and exclusion criteria were applied, according to Chart 1.

Chart 1 - Inclusion and exclusion criteria for publications.

At first, the selection of publications was made by analyzing the title, and summary of studies obtained as search results (step 1), followed by the elimination of duplicate results obtained in the different databases searched (step 2). Subsequently, the full version of the publications was read, and the inclusion and exclusion criteria were applied (step 3), aiming to establish the final selection of publications to be included in this research sample, according to the method used in Ribeiro’s study in 2019¹³.

In the publications that were part of the sample of this study, data were collected regarding sample size, mean age and patient follow-up, limb affected by lymphedema, previous period of presentation of symptoms, whether or not lymphadenectomy was performed during cancer treatment, in addition to the reduced volume percentage in the limbs affected by lymphedema. Studies like the one by Gharb et al., in 2011¹⁸, were excluded because, despite having a similar objective to this research, the percentages of reduction in circumference, perimeter, or volume in the limb affected by lymphedema in patients were not defined.

The collected data were submitted to a meta-analysis to formulate the results of this research, using the SPSS for Windows 15 software (IBM SPSS Software, New York, USA)

RESULTS

Searches in different databases resulted in 2,490 publications, which were reduced to 57 after the first stage of analysis (title and summary), 26 after the second stage (removal of duplicates) and, finally, 10 publications after the third stage (analysis of the full content of the articles), which fit the established inclusion and exclusion criteria.

Regarding the ten studies included in this meta-analysis sample, eight are specifically related to the results of autologous lymph node transplantation for the management of post-mastectomy upper limb lymphedema^{14,15,19-21,23-26}, while one compared these findings with the findings of patients undergoing only physical therapy¹⁷.

The publications included in this sample included 194 patients, who had 50.0 years average age, being followed up for 31.7 months average (Table 1).

Table 1 - General characteristics of the sample.

As shown in Table 2, most patients presented the right upper limb affected by lymphedema (58.1%), beginning the symptoms more than a year before the lymph node transplantation surgery (86.4%). Only four patients (2.6%) did not undergo lymphadenectomy during the treatment of breast cancer.

Table 2 - Characteristics related to lymphedema presented by the patients.

In general, lymph node transplantation was able to provide an average reduction of 52.18% in the excessive volume presented by patients in the limb as a result of lymphedema; in fact, most of the patients surveyed had a volume reduction higher than 50% (Table 3).

Table 3 - General characteristics of patients undergoing mastectomy associated with immediate reconstruction.

DISCUSSION

One of the factors that have motivated new research involving women undergoing breast cancer treatment is the occurrence of lymphedema in patients who undergo mastectomy^4-6,11,27,28, not yet being established all the etiological factors for such occurrence. Anyway, it is recognized that axillary lymph node dissection is a risk factor for the development of lymphedema after mastectomy^6,11-13,29, regardless of the surgical technique (simple mastectomy associated with axillary lymph node dissection or modified radical mastectomy)²⁹. In this study, it was found that the majority of patients included in the sample underwent lymphadenectomy (97.4%), which may have contributed to the development of upper limb lymphedema after treatment for breast cancer.

Therefore, even though many experts have sought risk and preventive factors, the occurrence of lymphedema after a mastectomy is still a reality in clinical practice^13-21,23-26, causing a loss in patients’ quality of life who develop it. Thus, lymph node transplantation has been used as one of the forms of treatment, improving lymphatic drainage from an affected limb in patients with damaged lymph nodes or hypoplastic lymphatic vessels16. Therefore, this study aimed to identify the rates of excessive volume reduction caused by lymphedema in the upper limbs of mastectomized patients submitted to autologous lymph node transplantation.

It is recognized that the association of mastectomy with immediate breast reconstruction can prevent the occurrence of post-mastectomy lymphedema^13,27,30,31. In this context, a study was found that evaluated the performance of lymph node transplantation simultaneously with breast reconstruction, concluding that this is a useful technique. It caused lymphatic recovery in 83.3% of the patients, without the need for additional posterior surgery, since the procedure had been performed in an associated manner²⁵.

Lymph node transplantation has been emphasized as a considerably effective method, especially when analyzing a study that compares patients who are treated only with physiotherapy and medications (reaching rates of 18% reduction in the volume of the affected limb), with patients undergoing the surgical procedure, of lymph node transplantation, which presented around 57%¹⁷. In general, the findings of this study corroborate the referred research, since it showed that the average percentage of reduction in volume was 52.18% and that most patients had more than half of the excessive circumference reduced after the transplant lymph node. Such findings encourage the indication of the technique since this represents a considerable reduction in the arms discrepancy presented by women with lymphedema and relief in the physical, social, and psychological symptoms of these patients.

It is important to note that, in the case of autologous transplants, lymph node donor sites may be compromised in the event of inadequate collection procedures, which could further aggravate patients’ situations for whom solutions are sought. In the study by Demiri et al., in 2018¹⁶, 1.6% (n = 3/189) of the patients developed lymphedema in the lymphatic flap’s lower limb donor. In the study by Viitanen et al., in 2012³², although none of the patients developed lymphedema at the donor site, the first post-surgical lymphoscintigrams indicated the need to reduce surgical trauma during the collection of the lymphatic flap. Thus, the importance of a detailed study about each case is mentioned here so that the decision making about the procedures to be adopted is duly based, in particular, on scientific evidence.

It is essential to mention that the technical and scientific evolution makes lymph node transplantation promising, especially when considering its association with other techniques. As an example, it is mentioned that the research presented the highest average percentage of excessive volume reduction in the limb affected by lymphedema in this study by Nicoli et al., in 2015²⁴ (91.5%), in which lymph node transplantation was associated with laser liposuction, enhancing the results and causing a more satisfactory immediate prognosis.

Finally, the need to conduct further research with the focus on the success rates of lymph node transplants for the management of lymphedema related to breast cancer is emphasized, especially with standardized methodologies and testing the associations with methods and technologies that can favor the results and improve the patients’ quality of life.

CONCLUSION

Considering the systematic review and meta-analysis carried out, it is concluded that autologous lymph node transplantation is a good option for the management of lymphedema related to breast cancer, providing a considerable reduction (52.18%) in the excessive volume of the affected limb.