Progression of fluid infiltration on non-contrast magnetic resonance imaging in breast cancer-related lymphedema: A comparative analysis with indocyanine green lymphography.

BACKGROUND: Non-contrast magnetic resonance imaging (NMRI) has been reported as valuable for the assessment of lymphedema. However, the correlation between NMRI findings and indocyanine green lymphography (ICG-L) findings remains elusive. METHODS: This single-center retrospective study included 26 patients diagnosed with breast cancer-related lymphedema. We examined the prevalence of fluid infiltration in eight regions of the upper extremity, the type of fluid distribution, and the dominant segment of edema on NMRI in comparison to the ICG-L stage. Statistical analysis was performed using the Cochran-Armitage trend test, Spearman's rank correlation test, and Fisher's exact test. RESULTS: The regional fluid infiltration significantly increased with the progression of the ICG-L stage (hand, forearm, elbow, and upper arm: p = 0.003, <0.001, <0.001, and <0.001, respectively). The fluid distribution significantly advanced with the progression of the ICG-L stage as follows (rs = 0.80; p < 0.001): no edema in ICG-L stage 0, edema in either the hand or elbow in ICG-L stage I, edemas in both the elbow and hand in ICG-L stage II, three segmental edemas centered on the forearm or elbow in ICG-L stage III, and edema encompassing the entire upper limb in ICG-L stage IV-V. Additionally, the dominant segment of edema tended to shift from the hand to the elbow and further to the forearm as the ICG-L stage progressed (p < 0.001). CONCLUSIONS: Fluid infiltration observed on NMRI exhibited distinct patterns with the progression of the ICG-L stage. We believe that anatomical information regarding fluid distribution would potentially contribute to optimizing surgical efficacy.

Effectiveness of lymphaticovenular anastomosis for adult-onset primary lower limb lymphedema: A retrospective study.

BACKGROUND: Surgical treatments such as lymphaticovenular anastomosis (LVA) are widely used in addition to conservative treatment of secondary lymphedema. However, their indications and effectiveness for primary lymphedema are unclear. This study aims to objectively demonstrate the effectiveness of LVA for adult-onset primary lymphedema from various perspectives. METHODS: We retrospectively examined patients with primary lower limb lymphedema who underwent LVA between January 2018 and December 2021 and were 21 or older. Treatment effects were evaluated using lymphoscintigraphy, questionnaires, body mass index, extracellular fluid ratio, and lymphedema index preoperatively and 6 months postoperatively. The LVA was performed under general anesthesia. RESULTS: We evaluated 11 patients (11 lower limbs). Out of seven patients with complete obstruction preoperatively, all presented partial obstruction according to the Taiwan Lymphoscintigraphy Staging classification with a significant decrease in the score. Significant improvements were observed in clinical symptoms ("hardness") and in quality of life ("appearance" and "ease of wearing compression garments") assessments. A significant change was observed in the extracellular water ratio but not in lower extremity lymphedema index (LELindex). CONCLUSION: LVA was suggested as one of the potential treatment options for patients with adult-onset primary lymphedema in whom lymphatic flow was confirmed by lymphoscintigraphy. In addition to clinical symptoms and physical examination, the evaluation of adult-onset primary lymphedema should include the patient's quality of life.

Preoperative photoacoustic versus indocyanine green lymphography in lymphaticovenular anastomosis outcomes for lower extremity lymphedema: A pilot study.

BACKGROUND: Identification of the proper lymphatics is important for successful lymphaticovenular anastomosis (LVA) for lymphedema; however, visualization of lymphatic vessels is challenging. Photoacoustic lymphangiography (PAL) can help visualize lymphatics more clearly than other modalities. Therefore, we investigated the usefulness of PAL and determined whether the clear and three-dimensional image of PAL affects LVA outcomes. METHODS: We recruited 22 female patients with lower extremity lymphedema. The operative time, number of incisions, number of anastomoses, lymphatic vessel detection rate (number of functional lymphatics identified during the operation/number of incisions), and limb volume changes preoperatively and 3 months postoperatively were compared retrospectively. The patients were divided according to whether PAL was performed or not, and results were compared between those undergoing PAL (PAL group; n = 10) and those who did not (near-infrared fluorescence [NIRF] group, n = 12). RESULTS: The mean age of the patients was 55.9 ± 15.1 years in the PAL group and 50.7 ± 14.9 years in the NIRF group. One patient in the PAL group and three in the NIRF group had primary lymphedema. Eighteen patients (PAL group, nine; and NIRF group, nine) had secondary lymphedema. Based on preoperative evaluation using the International Society of Lymphology (ISL) classification, eight patients were determined to be in stage 2 and two patients in late stage 2 in the PAL group. In contrast, in the NIRF group, one patient was determined to be in stage 0, three patients each in stage 1 and stage 2, and five patients in late stage 2. Lymphatic vessel detection rates were 93% (42 LVAs and 45 incisions) and 83% (50 LVAs and 60 incisions) in the groups with and without PAL, respectively (p = 0.42). Limb volume change was evaluated in five limbs of four patients and in seven limbs of five patients in the PAL and NIRF groups as 336.6 ± 203.6 mL (5.90% ± 3.27%) and 52.9 ± 260.7 mL (0.71% ± 4.27%), respectively. The PAL group showed a significant volume reduction. (p = .038). CONCLUSIONS: Detection of functional lymphatic vessels on PAL is useful for treating LVA.

Contrast-enhanced ultrasonography as an adjunctive method to ICG lymphography for functional lymphaticovenous anastomosis.

BACKGROUND AND OBJECTIVES: Indocyanine green (ICG) lymphography is the reference standard for evaluating lymphedema stage and identifying lymphatic vessels. However, the penetration depth was limited to 1-2 cm from the skin surface. This prospective study compares clinical outcomes following lymphaticovenous anastomoses (LVA) in patients with upper and lower limb lymphedema using contrast-enhanced ultrasonography (CEUS) with ICG as a preoperative imaging modality. METHODS: Under general anesthesia, Sonazoid® was injected subcutaneously to visualize functional lymphatic channels via CEUS. We analyzed the changes in limb circumference and inter-limb ratio (ILR) using bioimpedance to measure electrical resistance between the CEUS plus ICG group and the ICG-only group to see the effect of CEUS-assisted LVA. RESULTS: No significant demographic differences existed between the two groups (CEUS plus ICG group vs. ICG-only group). The ILR decrease of the Z1 value measured using bioimpedance was statistically significant (p = 0.042 for the upper limb, p = 0.002 for the lower limb)- CONCLUSIONS: CEUS allowed us to identify deep-lying, functional, and large lymphatic channels. In conclusion, the combination of CEUS and ICG for identifying lymphatic channels has the potential to lead to a more functional lymphovenous anastomosis.

Advances in lymphedema: An under-recognized disease with a hopeful future for patients.

Lymphedema has traditionally been underappreciated by the healthcare community. Understanding of the underlying pathophysiology and treatments beyond compression have been limited until recently. Increased investigation has demonstrated the key role of inflammation and resultant fibrosis and adipose deposition leading to the clinical sequelae and associated reduction in quality of life with lymphedema. New imaging techniques including magnetic resonance imaging (MRI), indocyanine green lymphography, and high-frequency ultrasound offer improved resolution and understanding of lymphatic anatomy and flow. Nonsurgical therapy with compression, exercise, and weight loss remains the mainstay of therapy, but growing surgical options show promise. Physiologic procedures (lymphovenous anastomosis and vascularized lymph node transfers) improve lymphatic flow in the diseased limb and may reduce edema and the burden of compression. Debulking, primarily with liposuction to remove the adipose deposition that has accumulated, results in a dramatic decrease in limb girth in appropriately selected patients. Though early, there are also exciting developments of potential therapeutic targets tackling the underlying drivers of the disease. Multidisciplinary teams have developed to offer the full breadth of evaluation and current management, but the development of a greater understanding and availability of therapies is needed to ensure patients with lymphedema have greater opportunity for optimal care.

Lymphatic remapping by long-term lymphoscintigraphy follow-up in secondary lymphedema after breast cancer surgery.

The purpose of the study is to investigate long-term changes on lymphoscintigraphy and their association with clinical factors in breast cancer-related lymphedema (BCRL) patients. This single-center cohort study included BCRL patients who underwent baseline and follow-up lymphoscintigraphy. The percentage of excessive circumference (PEC) of the affected upper limb compared with the unaffected side was used as an indicator of the clinical severity of BCRL. Each 99mTc-phytate lymphoscintigraphy image was categorized according to the Taiwan lymphoscintigraphy staging system. Clinical parameters and the lymphoscintigraphy stage at baseline and follow-up were compared and analyzed. Eighty-seven patients were included. Baseline and follow-up lymphoscintigraphies were performed at median 7 (interquartile range [IQR]: 2‒14) and 78 (IQR: 49‒116) months after surgery, respectively. Both lymphoscintigraphy stage and PEC showed variable change with overall increases in their severity. Stepwise multivariable analysis revealed follow-up lymphoscintigraphy stage (P = 0.001) to be independent variables for PEC at follow-up, however, baseline lymphoscintigraphy stage was not. The clinical courses of BCRL and patients' lymphoscintigraphy patterns showed diverse changes over long-term follow-up. In addition to initial lymphoscintigraphy for diagnosis, lymphatic remapping by follow-up lymphoscintigraphy can be useful to visualize functional changes in the lymphatic system that may guide the optimal management in BCRL.

Three-dimensional non-contrast magnetic resonance lymphography severity stage for upper extremity lymphedema.

PURPOSES: Non-contrast magnetic resonance lymphography (NMRL) has recently shown the capability of evaluating anatomical fluid distribution in upper extremity lymphedema (UEL). However, there is still a lack of knowledge about the correlation between the characteristic three-dimensional (3D) NMRL findings and the indocyanine green lymphography (ICG-L) findings. Our goal was to clarify the relationship between the 3D NMRL findings and the ICG-L findings. METHODS: Medical charts of patients with secondary UEL who underwent NMRL and ICG-L between January 2018 to October 2021 were reviewed. The upper extremities were divided into 6 regions; the hand, elbow, and the radial and ulnar aspects of the forearm and the upper arm. We investigated the prevalence of characteristic 3D NMRL patterns (Mist/Spray/Inky) in each region based on the ICG-L stage. We also examined the association between the 3D NMRL stage which we proposed and the ICG-L stage, and other clinical factors. RESULTS: A total of 150 regions of 25 patients with upper extremities lymphedema were enrolled in the study. All of the characteristic patterns increased significantly as the ICG-L stage advanced (p < 0.001, < 0.001, and < 0.001, respectively). The predominant NMRL patterns changed significantly from the Early pattern (Mist pattern) to the Advanced pattern (Inky/Spray pattern) as the ICG-L stage progressed (p < 0.001). The higher Stage of 3D NMRL was significantly associated with the progression of the ICG-L stage (rs = 0.80, p < 0.001). CONCLUSIONS: Characteristic 3D NMRL patterns and the 3D NMRL Stage had a significant relationship with the ICG-L stage and other clinical parameters. This information may be an efficient tool for a more precise and objective evaluation of various treatments for UEL patients.

Lymphedema after saphenous harvesting for coronary artery bypass surgery: case report and literature review.

Different causes have been described for secondary lymphedema as reported in this article. A 75-year-old man was diagnosed with lymphedema about one decade after saphenous harvesting for coronary artery bypass surgery. It took two years for him to find out his diagnosis and receive the proper treatment. After standard complete decongestive therapy, his volume and pain decreased and his quality of life was improved, especially its physical aspect. It is important to recognize the possibility of lymphedema development after saphenous harvesting among patients undergoing coronary artery bypass surgery to prevent significant disturbance of quality of life with timely management.

Efficacy of preoperative lymphoscintigraphy in predicting surgical outcomes of lymphaticovenous anastomosis in lower extremity lymphedema: Clinical correlations in gynecological cancer-related lymphedema.

BACKGROUND: Lymphaticovenous anastomosis (LVA) is a promising microsurgical treatment for lower extremity lymphedema (LEL). Lymphoscintigraphy effectively assesses lower limb lymphatic systems before LVA, but its role in predicting the therapeutic outcomes of LVA is indeterminate. In this study we investigate the efficacy of preoperative lymphoscintigraphy using clinical findings to predict outcomes in gynecological cancer-related LEL patients who underwent LVA. METHODS: A retrospective review was conducted on consecutive gynecological cancer patients with LEL who had undergone LVA between June 2018 and June 2021. The therapeutic efficacy was assessed by measuring the change rate of the lower extremity lymphedema index (LELi) six months after surgery. Clinical data and lymphoscintigraphic findings were analyzed to assess therapeutic efficacy of LVA. RESULTS: Out of the 60 evaluated legs, 83.3% of the legs showed improved results after LVA. Univariable linear regression analysis revealed that higher preoperative LELi, and ovarian cancer were associated with superior LELi change rate (LC rate). Absence of dermal backflow (DBF) on lymphoscintigraphy was associated with inferior LC rate. Multivariable linear regression analysis identified ovarian cancer and higher preoperative LELi were independently correlated with favorable outcomes, while the absence of DBF was independently correlated with inferior outcomes. CONCLUSION: The results of this study emphasizes the effectiveness of preoperative lymphoscintigraphy, preoperative LELi, and primary malignancy as predictors of LVA outcomes in gynecological cancer-related LEL patients.

Application of combined preoperative indocyanine green lymphography and ultrasonography for low-pressure vein localization in secondary lymphedema surgery for breast cancer.

BACKGROUND: This study aimed to investigate the value of preoperative indocyanine green (ICG) lymphography combined with ultrasonography for low-pressure vein localization in secondary lymphedema surgery for breast cancer. METHODS: A total of 29 patients who were admitted to the breast surgery department of our hospital from July 2019 to May 2021 were included in this study. All patients received preoperative reverse lymphography and ultrasonography for low-pressure vein in lymphedema surgery. Three arm circumferences were measured before surgery, 6 months after surgery, and 12 months after surgery for comparison with the healthy limb at the same time. RESULTS: Arm circumference at 12 months after surgery was significantly different from those at the preoperative period and 6 months after surgery (P < 0.05). However, this parameter after surgery was still significantly higher than that of the healthy limb (P < 0.05). CONCLUSIONS: The application of preoperative ICG lymphography combined with ultrasonography for low-pressure vein localization before surgery can greatly shorten operation duration by reducing the number of ineffective incisions and improving the probability of vein-lymphatic vessel matching, while ensuring the postoperative efficacy for patients.

Overlapping lockup lymphaticovenous anastomosis: A useful addition to supermicrosurgery.

BACKGROUND: Lymphaticovenular anastomosis (LVA) is a minimally invasive surgical procedure used to treat lymphedema. This surgical procedure connects the superficial lymphatic vessels to nearby veins to establish lymphatic-venous pathways. One of the most common challenges encountered by lymphatic surgeons when performing LVA is a mismatch in the sizes of the veins and lymphatic vessels, with the effectiveness limited by technical constraints. We conducted a pilot study to evaluate the feasibility of an overlapping lockup anastomosis (OLA) LVA technique to address these problems. METHODS: In this study, we present a novel OLA technique for LVA that addresses the challenges with conventional techniques. The OLA technique was used in 10 lymphedema patients between September 2022 and March 2023 to compare OLA and end-to-end anastomosis. The time required for anastomosis, method of anastomosis, patency rates, and lymphedema volume were evaluated in this study. RESULTS: Of 123 LVAs, 44 were performed using the OLA technique in 10 patients, with indocyanine green lymphangiography revealing unobstructed drainage. A single case of slight fluid leakage occurred, which was resolved by reinforcing the sutures. The average anastomosis time for OLA and the end-to-end technique was 5.55 minutes and 12.1 minutes, respectively. The wounds of the patients healed without infection, and the subjective limb circumference decreased. CONCLUSIONS: The OLA technique could serve as a valuable addition to the current LVA technique, especially for cases with a mismatch in the sizes of the lymphatic vessels and veins. This technique has the potential to promote the broader application of LVA in the treatment and prevention of lymphedema.

Biomaterials in the clinical treatment of lymphedema-a systematic review.

OBJECTIVE: Lymphedema is a chronic condition caused by impaired lymphatic fluid drainage, resulting in progressive edema. The current mainstay of lymphedema therapy consists of conservative therapy and surgical therapy. In this systematic review, we investigated the novel role of biomaterials in clinical lymphedema therapy and assessed their objective outcomes and the complication rate associated with their use. METHODS: Studies were identified through systematic review using the Embase and PubMed/MEDLINE databases. Only original articles reporting the use of biomaterials for clinical lymphedema therapy were included. The primary outcome measure was the objective reduction in limb volume after biomaterial use. The secondary outcome measure was the assessment of biomaterial safety. RESULTS: A total of 354 articles were identified in the first search, of which 10 met our inclusion criteria. These articles described the use of two biomaterials, nanofibrillar collagen scaffolds (NCSs) and silicone tubes (STs), for the treatment of lymphedema. NCS implantation showed an average excess limb volume reduction of 1% to 10.7% and clear evidence of lymphangiogenesis on imaging. No complications were 7documented after NCS implantation. ST implantation showed an average limb volume reduction of 700 to 887 mL and limb circumference reduction of 3.1 to 8 cm in patients with advanced stage lymphedema. Of 177 patients treated with ST implantation, only 11 (6.2%) developed local inflammation. CONCLUSIONS: Both NCS and ST implantation showed promising limb volume reduction; however, with the scarce literature available, additional research is needed to determine their effectiveness. Both demonstrated good safety profiles, with no complications after NCS implantation and a complication rate equivalent to other similar implants for ST implantation.

Current and Developing Lymphatic Imaging Approaches for Elucidation of Functional Mechanisms and Disease Progression.

Study of the lymphatic system, compared to that of the other body systems, has been historically neglected. While scientists and clinicians have, in recent decades, gained a better appreciation of the functionality of the lymphatics as well as their role in associated diseases (and consequently investigated these topics further in their experimental work), there is still much left to be understood of the lymphatic system. In this review article, we discuss the role lymphatic imaging techniques have played in this recent series of advancements and how new imaging techniques can help bolster this wave of discovery. We specifically highlight the use of lymphatic imaging techniques in understanding the fundamental anatomy and physiology of the lymphatic system; investigating the development of lymphatic vasculature (using techniques such as intravital microscopy); diagnosing, staging, and treating lymphedema and cancer; and its role in other disease states.

Optimal Cut-Off Value for Detecting Breast Cancer-Related Lymphedema Using Ultrasonography.

Background: We previously devised an ultrasonographic evaluation to calculate subcutaneous tissue cross-sectional area (△CSA). The reliability and accuracy of this method were demonstrated in healthy individuals and in patients with lymphedema. The purpose of this study was to estimate the optimal cut-off value of the ratio of the △CSA of the involved side (lesion side) to the contralateral side for detecting breast cancer-related lymphedema (BCRL) using ultrasonography. Methods and Results: Ultrasonographic measurements were performed 290 times in 150 patients. BCRLD was defined as a confirmed difference of >2 cm in arm circumference. BCRL confirmed by a clinician (BCRLC) was defined as the patient group that included not only BCRLD but also patients with subcutaneous thickening and abnormal findings on lymphoscintigraphy, even if the difference in arm circumference was <2 cm. The △CSAs of both upper arms and forearms were calculated by measuring the thickness of the subcutaneous tissue at four locations using ultrasonography (superior, medial, inferior, lateral) at 10 cm above the elbow and 10 cm below the elbow. With a 1.35 △CSA ratio as the cut-off value for detecting BCRLD, the sensitivity, specificity, and area under the receiver operating characteristic curve (AUC) were 0.88, 0.87, and 0.95, respectively. With a 1.20 △CSA ratio as the cut-off value for detecting BCRLC, the sensitivity, specificity, and AUC were 0.92, 0.89, and 0.97, respectively. Conclusions: Our findings suggest that a 1.20 △CSA ratio as determined using ultrasonography, corresponding to a tape measurement of 1.05 cm, can be considered as a diagnostic criterion for lymphedema.

Longitudinal Pattern of Lymphedema and Fibrosis in Patients With Oral Cavity or Oropharyngeal Cancer: A Prospective Study.

PURPOSE: The study aimed to describe the prevalence, severity, and trajectory of internal lymphedema, external lymphedema, and fibrosis in patients with oral cavity or oropharyngeal (OCOP) cancer. METHODS AND MATERIALS: One hundred twenty patients with newly diagnosed OCOP cancer were enrolled in a prospective longitudinal study. Recruitment was conducted at a comprehensive medical center. Participants were assessed pretreatment; at end of treatment; and at 3, 6, 9, and 12 months post-cancer treatment. Validated clinician-reported measures and computed tomography were used to assess the study outcomes. RESULTS: Seventy-six patients who completed the 9- or 12-month assessments were included in this report. Examination of the external lymphedema and fibrosis trajectories revealed that the total severity score peaked between the end of treatment and 3 months posttreatment and then decreased gradually over time but did not return to baseline by 12 months posttreatment (P < .001). The longitudinal patterns of severity scores for patients treated with surgery only or with multimodality therapy were similar. Examination of the internal swelling trajectories revealed that all patients experienced a significant increase in sites with swelling immediately posttreatment. For patients treated with surgery only, swelling was minimal and returned to baseline by 9 to 12 months posttreatment. Patients receiving multimodal treatment experienced a gradual decrease in number of sites with swelling during the 12-month posttreatment period that remained significantly above baseline (P < .05). Computed tomography revealed different patterns of changes in prevertebral soft tissue and epiglottic thickness in the surgery-only and multimodality treatment groups during the 12-month posttreatment period. There were minimal changes in thickness in both regions in the surgery-only group. Patients with multimodal treatment had significant increases in thickness in both regions 3 months posttreatment that remained thicker at 12 months than at baseline (P < .001). CONCLUSIONS: Lymphedema and fibrosis are the common complications of OCOP cancer therapy. Routine assessment, monitoring, and timely treatment of lymphedema and fibrosis are critical.

Evaluation of Primary Lymphedema with Intranodal Lymphangiography.

PURPOSE: There are limited existing data on the lymphatic anatomy of patients with primary lymphedema (LED), which is caused by aberrant development of lymphatic channels. In addition, there is a paucity of contemporary studies that use groin intranodal lymphangiography (IL) to evaluate LED anatomy. The purpose of this retrospective observational study was to better delineate the disease process and anatomy of primary LED using groin IL. MATERIALS AND METHODS: We identified common groin IL findings in a cohort of 17 primary LED patients performed between 1/1/2017 and 1/31/2022 at a single institution. These patients were clinically determined to have primary lymphedema and demonstrated associated findings on lower extremity MR and lymphoscintigraphy. RESULTS: Ten patients (59%) demonstrated irregular lymph node morphology or a paucity of lymph nodes on the more symptomatic laterality. Eight patients (47%) demonstrated lymphovenous shunting from pre-existing anastomoses between the lymphatic and venous systems. Eight patients (47%) demonstrated passage of contrast past midline to the contralateral lymphatics. Finally, 12 patients (71%) failed to opacify the cisterna chyli and thoracic duct on their initial lymphangiograms. Delayed computed tomography of 3 patients showed eventual central lymphatic opacification up to the renal veins, but none of these patients showed central lymphatic opacification to the thorax. CONCLUSION: This descriptive, exploratory study demonstrates common central groin IL findings in primary LED to highlight patterns interventional radiologists should identify and report when addressing primary LED.

A new lymphography protocol and interpretation principles based on functional lymphatic anatomy in lower limb lymphedema.

Indirect lymphatic system imaging is essential for diagnosing lymphatic diseases. The basic methodology involves intradermal or subcutaneous injection of a contrast agent into the surrounding lymphatic capillary, and the flow of the contrast agent is identified using a detector. Many contrast agents that use near-infrared dye, including indocyanine green (ICG) fluorescent lymphography, are available. ICG is rapidly spreading as a convenient and safe lymphedema diagnostic method, because it does not involve radiation exposure, and the imaging equipment is more compact than other devices. The lymphatic system is a semi-open circulatory system with numerous lymphatic capillaries acting as blind ends. Anatomical information on the injection site and observation of specific lymphatic vessels and nodes is important. However, this anatomical information is lacking. Recent reports suggest that ICG fluorescent lymphography can be applied to cadavers in the same manner as living bodies. Furthermore, these reports have demonstrated the functional aspects of the capillary lymph vessel networks as well as their relationship with lymphatic vessels and lymph nodes. This review article describes the historical progression from the old to the new functional lymphatic anatomy and introduces a new functional lymphography technique for the lower limbs.