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Management of Recurrent Leg Swelling in an Elderly Patient with Invasive Urothelial Carcinoma: Examining the Challenges of Post-Lymphovenous Anastomosis in Treating Cancer-Related Lymphedema

International Microsurgery Journal. 2024;8(1):1
DOI: 10.24983/scitemed.imj.2024.00179
Article Type: Case Report

Abstract

Various modalities for cancer treatment, including tumor resection surgery and adjuvant chemotherapy, can disrupt the lymphatic drainage in the lower extremities, potentially causing lymphedema. This report details a case of a 79-year-old female patient who underwent a series of procedures including transurethral incision of the ureteral orifice, laparoscopic nephroureterectomy, and adjuvant chemotherapy, as treatment for invasive urothelial carcinoma. Following these treatments, the patient developed symptoms of lower limb edema, later diagnosed as lymphedema via lymphoscintigraphy. The patient's lower extremity lymphedema initially improved following lymphovenous anastomosis. However, the edematous condition recurred after one year. Initially, the patient was presumed to have recurrent lymphedema, a logical assumption given that around 36% of patients necessitate revision of postoperative anastomosis. However, the subsequent diagnosis of deep vein thrombosis, followed by its appropriate treatment, led to an improvement in the lower extremity edema. This case highlights the significant risk of misdiagnosing deep vein thrombosis as recurrent lymphedema in patients who have undergone lymphovenous anastomosis, primarily due to the clinical similarities between the two conditions. Such misdiagnoses can lead to considerable delays in the administration of appropriate treatment for deep vein thrombosis. This study underscores the critical necessity of conducting a comprehensive reassessment in older cancer patients experiencing recurrent leg swelling following lymphovenous anastomosis. It also stresses the importance of accurately differentiating between a recurrence of lymphedema and other potential complications, such as deep vein thrombosis, to ensure the provision of timely and effective treatment.

Keywords

  • Deep vein thrombosis; hematuria; lymphedema; pembrolizumab; urothelial carcinoma

Introduction

In the postoperative management of lymphovenous anastomosis (LVA), initially suspecting lymphedema recurrence as the primary cause of re-emerging symptoms is a logical and methodologically sound practice. However, this standard approach may inadvertently overshadow other diagnoses, especially in cancer patients who are undergoing various treatments. A key diagnostic challenge arises in distinguishing between recurrent lymphedema and lower extremity swelling indicative of deep vein thrombosis (DVT). The latter may be a side effect of immunotherapeutic regimens commonly used in cancer treatment [1,2]. The clinical presentation of both conditions is often similar, with swelling being a common symptom, leading to frequent misdiagnoses.

Empirical evidence suggests that a considerable number of patients receiving cancer immunotherapy, about one-fourth, experience venous thromboembolism, which correlates with decreased overall survival rates [1]. Additionally, case studies have shown that patients with urothelial carcinoma can develop thrombotic microangiopathy in association with pembrolizumab therapy post-immunotherapy [2]. This evidence underscores the importance of considering a patient's immunotherapy history when diagnosing lower extremity edema, highlighting the potential for misdiagnoses that could delay critical DVT interventions.

This report presents a case study of an elderly patient post-LVA surgery, illustrating the complexities in post-surgical care. We explore the diagnostic process, interventional strategies, and the necessity for nuanced decision-making, especially in managing geriatric patients. This case study aims to illuminate the intricacies of postoperative care in oncologic surgery and emphasizes the need for tailored patient management strategies in the context of complex surgical histories.

Case Presentation

In December 2019, a 79-year-old female patient presented with hematuria. Her medical history was notable for hypertension, diabetes (managed with vildagliptin), and hepatitis C. An ultrasound, revealing hydronephrosis in her left kidney, led to further investigations including abdominal and pelvic computed tomography and a retrograde pyelogram, primarily to explore the possibility of renal stones. However, subsequent ureterorenoscopic stone manipulation resulted in a pathology report diagnosing left invasive urothelial carcinoma.

In February 2020, the patient underwent a dual surgical procedure consisting of a transurethral incision of the ureteral orifice and laparoscopic nephroterectomy. The pathological examination post-surgery confirmed high-grade invasive urothelial carcinoma extending from the ureter to the renal pelvis, classified as pathologic grade T3. Following surgery, in March 2020, she commenced an adjuvant chemotherapy regimen, comprising eight cycles of gemcitabine and carboplatin.

In March 2021, the patient sought medical attention for persistent bilateral lower limb edema, which had been ongoing for eight months and was more pronounced in her left leg. Despite the lack of DVT findings in the abdomen and pelvis computed tomography scans, her history of stage III invasive urothelial carcinoma, along with previous surgery and chemotherapy, necessitated further investigation. A lymphoscintigraphy examination was conducted, revealing partial mild lymphatic obstructions in both lower extremities (right P-1, left P-1, according to the Taiwan Lymphoscintigraphy Staging [3]). Clinically, both legs were categorized as stage II lymphedema, based on the International Society of Lymphedema staging [4].

After four months of conservative treatment, including compression garments, with no significant improvement, the patient underwent LVA on her left leg. A total of six side-to-end LVAs were performed, involving three in the left dorsal foot, one in the left lower leg, one in the left thigh, and one in the left lower abdomen (Figure 1). A compression garment was applied immediately after the operation. The postoperative course proceeded smoothly, and the patient was given empirical antibiotic cefazoline and pain control for three days. She was discharged three days post-surgery and scheduled for regular follow-ups in the outpatient clinic. At the follow-up on postoperative day 8, there was a noticeable improvement in edema in both legs (left leg reduced from 33.3 ± 10.7 cm to 26.2 ± 8.5 cm, right leg from 29.6 ± 7.9 cm to 27.5 ± 7.8 cm).

 

Figure 1. Three lymphovenous anastomoses (indicated by black arrows) are present in the dorsal foot wound during lymphovenous anastomosis surgery.

 

In March 2022, seven months post-LVA surgery, the patient began an 11-cycle pembrolizumab treatment due to tumor progression. Concurrently, she experienced recurrent swelling in her left leg, persisting for eight months before she sought help at the emergency department in November 2022. Upon examination, her left leg exhibited a swollen appearance, mild reddish skin, and discharge formation. Vascular sonography of the left lower limb revealed a partial thrombus in the left common femoral vein. Initially, Edoxaban was administered, temporarily alleviating the symptoms.

However, two months later, the patient returned to the emergency department with worsened pain and swelling in her leg. She was diagnosed with recurrent DVT and leg cellulitis. Initial vascular ultrasonography and computed tomography angiography identified a mural thrombus in the left common femoral vein, with a patent popliteal and calf vein. Subsequently, percutaneous transluminal angiography revealed bilateral common iliac vein occlusion. The patient underwent stent placement, which resulted in a reduction of the swelling in both legs postoperatively (Figure 2).

 

Figure 2. Comparative images showing the condition before (panel A) and after (panel B) treatment of deep vein thrombosis in the bilateral common iliac femoral veins. Post-treatment, there is a noticeable reduction in swelling in both legs.

Discussion

LVA has been established as an effective intervention for improving lower limb lymphedema, as evidenced in recent studies [5,6]. However, approximately 36% of patients require postoperative anastomosis revision [7]. Therefore, it is both reasonable and sensible to first consider lymphedema recurrence as the main concern when patients, who have undergone LVA, exhibit returning symptoms. Nevertheless, this approach entails a significant risk: Owing to their clinical similarities, patients who have undergone LVA and subsequently develop DVT are at a high risk of misdiagnosis as cases of recurrent lymphedema. Such misdiagnoses can lead to significant delays in the appropriate treatment for DVT. This study aims to underscore the critical need for thorough reassessment in older cancer patients who experience recurrent leg swelling after undergoing LVA. It highlights the importance of distinguishing between lymphedema recurrence and other potential complications like DVT to ensure timely and accurate treatment.

The primary complications associated with LVA include failed anastomosis, venous reflux, and cellulitis [7]. In clinical practice, when encountering patients with lymphedema who have previously undergone LVA and present with swollen feet, the initial diagnostic considerations typically focus on lymphedema recurrence and infection. Conversely, DVT is not commonly considered a primary diagnosis due to its relative infrequency as a complication of LVA.

However, this case presented additional risk factors that increased the patient's susceptibility to thrombosis-related edema. Notably, age was a significant risk factor for this 79-year-old patient [8]. Research indicates a substantial rise in DVT incidence among patients aged 70 and above [9]. Additionally, the patient's decreased mobility, a consequence of leg swelling, might have further heightened her risk of developing DVT [10]. This case serves as a reminder to clinicians that even when a patient has a well-documented history of LVA, commonly associated with leg edema, a thorough reassessment of the vascular system is essential to ensure an accurate and comprehensive diagnosis of thrombosis-related edema.

Upon reviewing the patient’s medical history, we observed a significant overlap between the onset of foot swelling from DVT and her immunotherapy period with pembrolizumab. This coincidence has led us to consider the possibility that the immunotherapy may have contributed to the development of DVT. Notably, among patients undergoing cancer immunotherapy, nearly one-fourth experience venous thromboembolism, a condition that has been associated with a decrease in overall survival rates [1]. Additionally, a specific case report highlighted that patients with urothelial cancer developed pembrolizumab-associated thrombotic microangiopathy following immunotherapy [2]. These findings collectively indicate that a history of immunotherapy in patients may be a critical factor in the development of symptoms, such as swollen lower extremities.

Complex medical cases often involve patients suffering from both venous edema and lymphedema, as seen in phlebolymphedema. Phlebolymphedema, characterized by swelling due to a combination of chronic venous insufficiency and lymphatic insufficiency, is the most prevalent form of lymphedema in the Western world [11]. Chronic venous insufficiency can develop from venous valve inefficiency, blockages, or a combination of these factors. Furthermore, dysfunction in the muscle pump, particularly in the calf muscles, can exacerbate these conditions [12]. Therefore, it is crucial to maintain vigilance for chronic venous insufficiency both before and after treating lymphedema. Key risk factors for chronic venous insufficiency include age, a family history of venous disease, indicators of ligamentous laxity (e.g., history of hernia surgery, flat feet), body weight, level of physical activity, and smoking [13]. Recognizing and addressing these risk factors are essential steps in the comprehensive management of patients with lymphedema or phlebolymphedema.

The key takeaway from this case is the critical importance of a comprehensive and systematic assessment in patients with complex medical histories. Despite the patient's history suggesting lymphedema recurrence as the primary cause of her foot swelling, the necessity to conduct a thorough evaluation of her venous and lymphatic systems, infection status, and cancer treatment history is paramount. This holistic approach is essential to ensure accurate diagnosis and effective management of the patient's condition. It highlights the need to consider the complexity of the patient’s medical background and the possibility of overlapping symptoms from various conditions. Such an approach is vital in avoiding misdiagnosis and in providing the most effective treatment strategy tailored to the patient's unique medical needs.

Conclusion

In cases of recurrent edema in elderly cancer patients who have previously undergone LVA surgery for lymphedema, it is crucial to consider and rule out phlebolymphedema and DVT as possible causes. To achieve a comprehensive diagnosis, additional assessments like vascular sonography or computed tomography angiography should be conducted. These diagnostic tools can help exclude other potential etiologies and ensure that the patient receives the most appropriate and effective treatment. This approach is vital for a holistic patient care strategy, particularly given the complex interplay of factors in such patients.

References

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  2. Hayata M, Shimanuki M, Ko T, et al. Pembrolizumab-associated thrombotic microangiopathy in a patient with urothelial cancer: A case report and literature review. Renal Replacement Therapy 2020;6(1):29. [View Article]
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  12. Eberhardt RT, Raffetto JD. Chronic venous insufficiency. Circulation 2014;130(4):333–346. [View Article]
  13. Criqui MH, Denenberg JO, Bergan J, Langer RD, Fronek A. Risk factors for chronic venous disease: The San Diego Population Study. J Vasc Surg 2007;46(2):331–337. [View Article]

Editorial Information

Publication History

Received date: November 28, 2023
Accepted date: January 09, 2024
Published date: January 17, 2024

Disclosure

The manuscript has not been presented or discussed at any scientific meetings, conferences, or seminars related to the topic of the research.

Ethics Approval and Consent to Participate

The study adheres to the ethical principles outlined in the 1964 Helsinki Declaration and its subsequent revisions, or other equivalent ethical standards that may be applicable. These ethical standards govern the use of human subjects in research and ensure that the study is conducted in an ethical and responsible manner. The researchers have taken extensive care to ensure that the study complies with all ethical standards and guidelines to protect the well-being and privacy of the participants.

Funding

The author(s) of this research wish to declare that the study was conducted without the support of any specific grant from any funding agency in the public, commercial, or not-for-profit sectors. The author(s) conducted the study solely with their own resources, without any external financial assistance. The lack of financial support from external sources does not in any way impact the integrity or quality of the research presented in this article. The author(s) have ensured that the study was conducted according to the highest ethical and scientific standards.

Conflict of Interest

In accordance with the ethical standards set forth by the SciTeMed publishing group for the publication of high-quality scientific research, the author(s) of this article declare that there are no financial or other conflicts of interest that could potentially impact the integrity of the research presented. Additionally, the author(s) affirm that this work is solely the intellectual property of the author(s), and no other individuals or entities have substantially contributed to its content or findings.

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Department of Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan
Department of Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan
Division of Cardiology, Department of Internal Medicine, National Taiwan University Hospital Yunlin Branch, Yunlin County, Taiwan
Division of Plastic Surgery, Department of Surgery, National Taiwan University Hospital Yunlin Branch, Yunlin County, Taiwan
Division of Plastic Surgery, Department of Surgery, National Taiwan University Hospital Yunlin Branch, Yunlin County, Taiwan
Email: yingshenglin@gmail.com
Address: No. 579, Section 2, Yunlin Road, Douliu City, Yunlin County, Taiwan
Figure 1.JPG
Figure 1. Three lymphovenous anastomoses (indicated by black arrows) are present in the dorsal foot wound during lymphovenous anastomosis surgery.
Figure 2.JPG
Figure 2. Comparative images showing the condition before (panel A) and after (panel B) treatment of deep vein thrombosis in the bilateral common iliac femoral veins. Post-treatment, there is a noticeable reduction in swelling in both legs.

Reviewer 1 Comments

In this study, the researchers analyze the intricate interplay among various cancer treatment methods, the emergence of lymphedema, and the incidence of deep vein thrombosis (DVT). The patient in focus initially received treatment for invasive urothelial carcinoma, undergoing procedures such as transurethral incision of the ureteral orifice, laparoscopic nephroureterectomy, and adjuvant chemotherapy. Following these treatments, she developed lower limb edema, which was later diagnosed as lymphedema through lymphoscintigraphy. Despite temporary alleviation through lymphovenous anastomosis (LVA), the edema resurfaced after a year. A significant development occurred when the patient was diagnosed with DVT, for which she received effective treatment, leading to the resolution of the lower extremity edema. This case highlights the complex relationship between cancer-related lymphedema and lower extremity edema, accentuating the necessity to consider additional factors such as age, cancer history, and sedentary lifestyle. It also alerts healthcare professionals to the possibility of DVT as a contributing factor, especially in cases of recurring edema following LVA. The report merits publication in an academic journal due to its clinical importance and educational contribution. Nevertheless, certain aspects warrant consideration prior to its publication.

  1. The report indicates that DVT might be a complication following LVA surgery in patients with lymphedema related to cancer. It would be useful for the authors to clarify whether this association is supported by existing research or if this specific case represents a unique instance.
    ResponseThank you for your valuable feedback. We appreciate your suggestion to clarify the association between DVT and LVA surgery in patients with cancer-related lymphedema. Our initial discussion was based on existing literature mentioning potential post-operative DVT occurrences following lymphatic microsurgery, specifically addressing factors such as Intima-to-Intima Coaptation and the Compliance Concept. Upon further investigation and consideration of your comments, we did not find direct evidence in the literature supporting a causal link between LVA surgery and DVT. In light of this, we decided to remove any speculative statements regarding LVA as a potential cause of DVT. In our case, the overlapping periods of immunotherapy and the recurrence of lower limb edema led us to reconsider, with a leaning towards immunotherapy as a more likely primary factor contributing to DVT in the patient.
     
  2. The authors note that they did not perform regular venous ultrasound tests on patients who had a well-documented history of cancer treatment and positive results from lymphoscintigraphy. This decision to skip these ultrasound exams might be seen as a neglect of proper patient care, especially because there's a risk of patients with cancer-related lymphedema also having DVT at the same time.
    ResponseWe apologize for any concerns raised by the reviewer, and we acknowledge the significance of addressing DVT in cancer patients. We also appreciate and will take to heart the valuable feedback provided. During the patient's initial presentation in March 2021 with lower limb swelling, our decision to focus on lymphedema management was based on the consideration of precise evidence from lymphoscintigraphy. It is crucial to emphasize that, without improvement post-LVA, DVT would have been included in the diagnostic considerations. Upon revisiting the patient's case, several reasons support the assertion that the swelling observed in March 2021 was attributed to lymphedema, thus demonstrating that the DVT identified in November 2022 was not a previously overlooked diagnosis. Firstly, the patient experienced significant improvement in limb swelling following the LVA surgery, with a recurrence occurring over a year later. Secondly, the patient reported ongoing swelling symptoms from early 2021 until the August visit, and abdominal and pelvic CT scans during that period did not reveal DVT. Consequently, we infer that the left common femoral vein mural thrombus identified in November 2022 was a newly developed DVT. Lastly, the timing of the second episode of leg swelling correlated closely with the initiation of new immunotherapy using pembrolizumab, providing a reasonable basis to consider immunotherapy as a potential cause of the subsequent DVT.
     
  3. Would it be possible to offer more background on the patient's medical history, particularly regarding her high-grade invasive urothelial carcinoma diagnosis? Details like the stage of her cancer would be very helpful in understanding the full context of the case report. Additionally, a clearer description of her current health status, especially concerning any conditions such as diabetes or hypertension, is needed for a comprehensive analysis.
    ResponseThank you for your insightful feedback. In response to your suggestions, we have expanded the details of the patient's medical history, specifically elaborating on her high-grade invasive urothelial carcinoma diagnosis. In lines 49-59 and 78-81, you will find a more comprehensive description that includes the stage of her cancer, providing a clearer context for the case report. Furthermore, we have provided additional information on the patient's current health status, paying specific attention to conditions such as diabetes and hypertension. We believe these additions contribute to a more thorough analysis of the case.

Reviewer 2 Comments

The case report focuses on an 80-year-old woman who presented with swelling in both lower limbs, notably more severe in her left leg. Her medical history included a high-grade invasive urothelial carcinoma in her left ureter and renal pelvis, treated through surgical and chemotherapeutic interventions. Despite these treatments, she developed progressive swelling in her lower extremities, which was later identified as lymphedema. She underwent lymphovenous anastomosis (LVA) surgery for this condition. However, the swelling recurred, leading to an emergency department visit where she was diagnosed with deep vein thrombosis (DVT). Subsequent treatment for DVT and stent placement helped alleviate the leg swelling. This case report underscores the diagnostic and management challenges of lower extremity edema in such scenarios. The report holds significant value for publication, given its clinical importance and educational contributions. Nonetheless, it is essential to address certain specific concerns before deeming it ready for publication.

  1. The report discusses but doesn't conclusively establish a causal connection between the cancer treatment and the onset of lymphedema. A more detailed exploration of this relationship, backed by existing literature and research, could strengthen the report.
    ResponseThank you for your valuable feedback. In response to your comments, we have provided additional details in lines 53-59 and 63-65 regarding the potential causal connection between cancer treatment and the onset of lymphedema. The patient underwent a combined procedure involving a transurethral incision of the ureteral orifice and a laparoscopic nephroterectomy with adjuvant chemotherapy. Considering this, we believe that lymphedema may be associated with surgery and chemotherapy. Furthermore, to support this observation, a lymphoscintigraphy examination was conducted, and the results revealed partial mild lymphatic obstructions in both lower extremities.
     
  2. The patient began to experience renewed swelling in her left leg seven months following her LVA surgery. Notably, it took approximately 15 months before DVT was considered a potential contributing factor. It would be beneficial to understand the initial inclination to attribute this recurring swelling primarily to a recurrence of lymphedema, rather than considering the possibility of DVT at an earlier stage.
    ResponseThank you for your valuable feedback. In response to your suggestion, we conducted an in-depth exploration of the postoperative complications related to LVA, and our findings suggest that the primary complications post-surgery are likely derived from failed anastomosis, leading to recurrent lymphedema, venous reflux, and cellulitis. In contrast, DVT is a less common complication. Therefore, we believe that excessive focus on the patient's history of LVA surgery might lead to a misdirection in diagnosis, potentially causing a delay in treatment—something we aim to prevent in this case report. We have incorporated these insights into the manuscript, specifically in lines 95-108.

Reviewer 3 Comments

This case report presents an insightful analysis of recurrent edema due to deep vein thrombosis (DVT) in a patient who underwent lymphovenous anastomosis (LVA) for cancer-related lymphedema. The patient, an elderly individual with a history of invasive urothelial carcinoma, developed bilateral lower limb lymphedema following cancer treatment. Post-LVA, there was an initial improvement in lymphedema, but the patient subsequently experienced a relapse, which was diagnosed as DVT. This case underscores the importance of considering DVT in patients with recurrent edema after LVA, particularly in elderly patients with risk factors such as a sedentary lifestyle. It also emphasizes the need for comprehensive vascular assessments in similar cases and suggests the inclusion of routine venous ultrasound for effective management. The case report is very informative, especially regarding the patient's medical progression. However, to enhance its suitability for publication, I would like to request additional clarification on several points.

  1. Could you please provide more details on the causal relationships between the various medical incidents detailed in the report? The sequence of events, including the onset of lower limb edema post-cancer treatment, LVA surgery for lymphedema, the recurrence of edema, and the final diagnosis and treatment of DVT, is well documented. I am particularly interested in understanding whether the initial cancer treatment directly led to the lymphedema, the potential role of LVA surgery in the development of DVT, and how these medical events are interconnected. Additional insights or information on the potential causative factors and their interactions in this case would be invaluable. Clarifying any uncertainties or limitations related to these causal connections would greatly enhance the report's comprehensiveness for readers.
    ResponseThank you for your detailed and thoughtful feedback. We appreciate your interest in the causal relationships among the various medical incidents detailed in the report. We have provided additional details in lines 53-59 and 63-65, specifically addressing the potential causal connection between cancer treatment and the onset of lymphedema. The patient underwent a combined procedure involving a transurethral incision of the ureteral orifice and a laparoscopic nephroureterectomy with adjuvant chemotherapy. Based on this information, we propose that lymphedema may be associated with surgery and chemotherapy. Regarding the potential role of LVA surgery in the development of DVT, our initial discussion referenced existing literature mentioning potential post-operative DVT occurrences following lymphatic microsurgery. We specifically addressed factors such as Intima-to-Intima Coaptation and the Compliance Concept. However, upon further investigation and considering your comments, we did not find direct evidence in the literature supporting a causal link between LVA surgery and DVT. Therefore, in light of this, we have decided to remove any speculative statements regarding LVA as a potential cause of DVT.
     
  2. It would be beneficial if you could provide references to similar cases in past literature that might support the causal relationships suggested in this report. Comparing this case to previous literature, or determining if this is a unique case, would be very helpful.
    ResponseThank you for your insightful suggestion. In response to your request, we have attempted to find references to similar cases in past literature that might support the causal relationships suggested in this report. Originally, we aimed to explore the theoretical possibility of DVT occurring in patients undergoing LVA. However, we found limited cases with similar circumstances. Upon careful examination, we believe that the DVT in this patient is more likely associated with the subsequent immunotherapy received, and there is supporting evidence from similar cases and studies. Additional details have been provided in lines 115-124 to elaborate on this perspective.
     
  3. The article suggests that DVT could be a potential complication in patients undergoing LVA for lymphedema. However, is it possible that the risk of DVT is not significantly higher in this patient group compared to other surgical procedures? In other words, might the benefits of LVA still outweigh the potential risks?
    ResponseThank you for your valuable inquiry. After reviewing relevant literature and case reports and considering the limited direct evidence of DVT occurrence post-LVA, we believe that the benefits of LVA still outweigh the potential risks. Despite the suggestion of DVT as a potential complication in patients undergoing LVA for lymphedema, the direct evidence supporting this claim is limited. LVA remains a crucial therapeutic surgery for lymphedema, and the benefits derived from its application, as supported by the available literature and case reports, continue to make it a valuable and important intervention.

Editorial Comments

  1. The authors mentioned that following a period of ineffective conservative treatments, including the use of compression garments, the patient proceeded to have lymphovenous anastomosis on her left leg. Could you specify the exact duration of this treatment phase before the surgery, such as one month?
    ResponseThank you for your valuable feedback. In response to your query regarding the exact duration of the conservative treatment phase before the surgery, we have included the information in lines 68-70 of the manuscript. The patient underwent approximately 4 months of ineffective conservative treatments, including the use of compression garments, before proceeding to lymphovenous anastomosis on her left leg.
     
  2. Could you clarify what is meant by “clear histories of cancer treatments” as used in the manuscript?
    ResponseThank you for seeking clarification on the phrase "clear histories of cancer treatments" used in the manuscript. The intended meaning of this statement is to convey that the patient developed lymphedema as a result of high-grade cancer following cancer treatment. Subsequently, the patient underwent LVA. We recognize that such a medical history may lead to a potential bias, directing the focus solely on recurrent lymphedema as the cause of the swelling leg, rather than considering vascular system disorders. In response to your feedback, we have revised the wording for accuracy and provided detailed explanations in lines 95-102.