Comparative analysis of the International Society of Lymphology and Taiwan Lymphoscintigraphy Staging systems: correlation, reliability, and a quantitative severity index in extremity lymphedema

Introduction

Lymphedema is a chronic condition characterized by the accumulation of lymphatic fluid leading to swelling, which severely affects the quality of life and functional capacity of patients (1). The accurate assessment and staging of lymphedema are essential for effective management and treatment planning. The main system used to classify lymphedema is the International Society of Lymphology (ISL) staging system (2,3). The ISL staging system, which is widely recognized and used worldwide, provides a standardized framework for classifying the severity of lymphedema based on clinical manifestations (2,3). It categorizes lymphedema into four stages, ranging from a subclinical stage to severe lymphedema with skin changes and complications. The system facilitates communication between healthcare providers and helps monitor disease progression (4). Conversely, the Taiwan Lymphoscintigraphy Staging (TLS) system was established more recently and provides a quantitative approach via the use of emission computed tomography (ECT) analysis. By combining detailed imaging and clinical criteria, this method allows for a more precise assessment of lymphatic obstruction in extremity lymphedema patients (5-8). However, due to its complexity, the TLS system is primarily suited for research purposes rather than routine clinical application, as the rigorous quantitative analysis can be more challenging to implement in day-to-day practice.

Given the different methodologies employed by the ISL staging system and the TLS system, the correlations between them need to be explored to ensure consistency in lymphedema assessment. Previous findings suggest that variations in the grading criteria and application of these systems may influence their alignment in clinical settings (9,10). Therefore, a comparative analysis could help identify potential discrepancies and contribute to the standardization of lymphedema evaluation. Moreover, assessing the inter- and intra-observer reliability of the TLS system is crucial to validating its application in research. Reliable grading is essential for accurate diagnosis, treatment planning, and outcome assessment. Ho et al. (11) reported variability in the application of these grading systems, highlighting the importance of establishing robust reliability measures.

In this study, we aimed to evaluate the correlation between the ISL staging system and the TLS system in extremity lymphedema. Additionally, we assessed the inter- and intra-observer reliability of the TLS system to determine its consistency in research settings. By conducting this research, we hope to contribute to the optimization of lymphedema assessment and management practices. Further, we also aimed to develop and validate a severity index that quantifies lymphedema by measuring limb circumference differences, adjusted for the body mass index (BMI), and analyze its correlation with both staging systems to distinguish between different severity levels. We present this article in accordance with the STROBE reporting checklist (available at https://qims.amegroups.com/article/view/10.21037/qims-24-1926/rc).

Methods

Study design

This retrospective study aimed to evaluate the correlation between the ISL staging system and the TLS system in patients with extremity lymphedema, and to develop a severity index based on limb circumference differences adjusted for the BMI. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013) and was approved by the Institutional Review Board of The First Affiliated Hospital of Sun Yat-sen University (No. [2023]299). All patients provided written informed consent for the use of their clinical data for research purposes.

Participants

We retrospectively reviewed the medical records of patients diagnosed with extremity lymphedema at The First Affiliated Hospital of Sun Yat-sen University between January 2018 and July 2024. To be eligible for inclusion in the study, the patients had to meet the following inclusion criteria: (I) be aged ≥18 years; (II) have a confirmed diagnosis of unilateral or bilateral extremity lymphedema; (III) have undergone lymphedema staging using both the ISL staging system and the TLS system; and (IV) have complete clinical records available, including imaging studies. Patients were excluded from the study if they met any of the following exclusion criteria: (I) had severe combined organ dysfunction or active infection; (II) had incomplete medical records; and/or (III) had undergone prior decongestive or surgical interventions for lymphedema before the staging assessment.

Data collection

Patients’ demographic data, including age, sex, BMI, and duration of lymphedema, were collected. The duration of lymphedema was defined as the time from the onset of symptoms to the date of the staging assessment. Lymphedema was staged using both the ISL staging system and the TLS system. The ISL staging system stages lymphedema based on clinical examination, while the TLS system incorporates additional imaging findings via ECT to provide a more precise yet complex classification. Additional parameters such as limb circumference, the presence of comorbidities (e.g., diabetes and hypertension), and a history of previous lymphedema treatment (e.g., compression therapy and manual lymphatic drainage) were also documented.

Staging assessment

The evaluation of lymphedema severity was performed using both the ISL staging system and the TLS system. Lymphoscintigraphy was performed by our colleagues at the Nuclear Medicine Department in accordance with the operational protocol of Cheng et al. (5). Four trained assessors—two microsurgeons and two radiologists—independently conducted the assessments. Under the ISL staging system, lymphedema is categorized into the following four stages based on the clinical findings:

• Stage 0 (latent): subclinical; swelling is not evident despite impaired lymph transport;
• Stage I (mild): early accumulation of fluid; subsides with limb elevation;
• Stage II (moderate): fluid accumulation, which does not subside on elevation; tissue fibrosis may have started;
• Stage III (severe): lymphostatic elephantiasis; significant skin changes.

Under the TLS system, lymphedema is categorized into the following different grades based on precise imaging findings from an ECT analysis (5):

• Grade L: normal lymphatic drainage (L-0);
• Grade P: partial obstruction;
  • P-1: distal linear lymphatic vessels without dermal backflow;
  • P-2: engorged distal linear lymphatic vessels with dermal backflow in the proximal or distal lymphedematous limb;
  • P-3: engorged lymphatic vessels with entire dermal backflow;
• Grade T: total obstruction:
  • T-4: engorged or absent lymphatic vessels with distal dermal backflow;
  • T-5: engorged or absent lymphatic vessels with dermal backflow in the entire limb;
  • T-6: absent lymphatic vessels without dermal backflow.

Both the ISL stage and TLS grade were evaluated in the same patients (Figures 1,2).

Figure 1 Images of three patients with lower-limb lymphedema. Patient A was ISL stage 1, and TLS grade P-2; Patient B was ISL stage 2, and TLS grade T-4; Patient C was ISL stage 3, and TLS grade T-6. ISL, International Society of Lymphology; TLS, Taiwan Lymphoscintigraphy Staging.

Figure 2 Images of three patients with upper-limb lymphedema. Patient A was ISL stage 1, and TLS grade P-2; Patient B was ISL stage 2, and TLS grade T-5; Patient C was ISL stage 3, and TLS grade T-6. ISL, International Society of Lymphology; TLS, Taiwan Lymphoscintigraphy Staging.

Assessment procedure

Each patient underwent a comprehensive assessment that included clinical examination, limb circumference measurement, and imaging studies (lymphoscintigraphy). The assessments were performed at the baseline and were repeated after four weeks to evaluate intra-observer reliability. To assess inter-observer reliability, all four assessors independently graded the lymphedema using the TLS system. The process was repeated after four weeks to assess intra-observer reliability, with each assessor re-evaluating the same patients without access to their initial assessments.

Subgroup analyses

Subgroup analyses were conducted to explore potential differences in the correlation between the ISL staging system and the TLS system based on specific patient characteristics. The subgroups were defined by:

• Affected limb: upper limb vs. lower limb;
• Etiology: secondary lymphedema vs. primary lymphedema;
• Duration of lymphedema: less than 5 vs. 5 years or more; and
• BMI: normal weight (BMI <25 kg/m²) vs. overweight/obese (BMI ≥25 kg/m²).

These analyses aimed to determine whether the correlation between the ISL staging system and the TLS system remained consistent across different patient populations.

Limb circumference measurement and severity index calculation

For patients with unilateral lymphedema, limb circumference was measured at several key anatomical points along the affected limb. These key points included the wrist/ankle, mid-forearm/mid-calf, and elbow/knee. The average circumference of these measurements was calculated. The same points were measured on the unaffected contralateral limb. The difference in the average circumferences between the affected and unaffected limbs was calculated, and then adjusted using the patient’s BMI to derive a severity index for lymphedema. As previous studies have already shown that the BMI is a risk factor for lymphedema, the use of the BMI adjustment may provide a more accurate representation of the severity (12-15).

The severity index was calculated as follows:

SeverityIndex=AverageCircumference(LymphedematousLimb−UninvolovedContralateralLimb)BMI[1]

This severity index was used to assess the severity of lymphedema, and its correlation with the ISL staging system and the TLS system was analyzed. Additionally, the severity index was compared across different ISL stages and TLS grades to determine whether there were statistically significant differences in severity between the stages and grades.

Statistical analysis

The statistical analysis was performed using SPSS version 26.0 (IBM Corp., Armonk, NY, USA). Descriptive statistics were used to summarize the demographic and clinical characteristics of the study population. The continuous variables are presented as the mean ± standard deviation (SD), or the median (interquartile range), while the categorical variables are presented as the frequency and percentage. The correlation between the ISL staging system and the TLS system, as well as the correlation between the severity index and both staging systems, was assessed using Spearman’s rank correlation coefficients. Subgroup analyses were performed to assess the consistency of the correlation across different patient populations. The severity index was compared across the ISL stages and TLS grades using a one-way analysis of variance (ANOVA) or the Kruskal-Wallis test as appropriate. The inter- and intra-observer reliability of the TLS system was evaluated using Cohen’s kappa coefficient (κ). A P value of <0.05 was considered statistically significant.

Results

Demographics and baseline characteristics of patients

In total, 50 patients were enrolled in this study, of whom 4 were male and 46 were female. The patients had a mean age of 56.1±12.9 years, a mean BMI of 24.7±3.6 kg/m², and a mean duration of lymphedema of 6.3±4.2 years. The distribution of lymphedema was as follows: 21 patients had left lower-limb lymphedema, 10 had left upper-limb lymphedema, 13 had right lower-limb lymphedema, 2 had right upper-limb lymphedema, and 4 had bilateral lower-limb lymphedema. Among these patients, 12 developed lymphedema secondary to breast cancer, 14 developed lymphedema secondary to cervical cancer, 4 developed lymphedema secondary to ovarian cancer, 7 developed lymphedema secondary to endometrial cancer, 4 developed lymphedema secondary to unclear gynecological tumors, 3 developed lymphedema secondary to bladder cancer, 1 developed lymphedema secondary to rectal cancer, and 5 had primary lymphedema. Additionally, 20 patients had comorbidities; specifically, 12 patients had hypertension and 8 patients had diabetes mellitus (Table 1).

Correlation between the severity index, ISL staging system and the TLS system

The correlation analysis showed significant agreement between the severity index, ISL staging system, and TLS system. The Spearman’s rank correlation coefficient between the ISL staging system and the TLS system was 0.49 (P=0.008), reflecting a correlation across all cases of extremity lymphedema. Moreover, the severity index was significantly correlated with both the ISL staging system and the TLS system, suggesting its potential use as an auxiliary parameter for assessing lymphedema severity. Specifically, the Spearman’s rank correlation coefficient between the severity index and the ISL staging system was 0.56 (P=0.001), and that of the TLS system was 0.37 (P=0.036) (Table 2).

Inter- and intra-observer reliability

Both the ISL staging system and the TLS system exhibited strong inter- and intra-observer reliability. Inter-observer reliability was assessed using the intraclass correlation coefficient (ICC), and the ICC of the ISL staging system was 0.92, while that of the TLS system was 0.90. Intra-observer reliability was similarly high, with ICC values of 0.94 and 0.93 for the ISL staging system and the TLS system, respectively. These findings suggest that both staging systems are highly reliable when used by different observers and by the same observer at different times (Table 3).

Staging distribution

In the ISL staging system, the distribution of patients was as follows: stage 0: 8%; stage I: 28%; stage II: 42%; and stage III: 22%. In the TLS system, the distribution of patients across the grades was as follows: grade P-1: 22%; grade P-2: 26%; grade P-3: 18%; grade T-4: 16%; grade T-5: 12%; and grade T-6: 6%. The similar staging distribution patterns across both systems further support the strong correlation between the ISL staging system and the TLS system (Table 4).

Subgroup analysis

The subgroup analysis revealed variations in the correlation between the ISL staging system and the TLS system based on patient characteristics. The correlation between the ISL staging system and the TLS system was stronger for lower-limb lymphedema (r=0.54) than upper-limb lymphedema (r=0.42) (P<0.001). Additionally, the correlation between the ISL staging system and the TLS system was stronger for primary lymphedema (r=0.45) than secondary lymphedema (r=0.55) (P<0.001). A longer disease duration (≥5 years) had a higher correlation with the ISL staging system (r=0.58) than the TLS system (r=0.34) (P<0.001), suggesting that more advanced disease may enhance the correlation with clinically based staging. No significant differences were found in the correlation between the ISL staging system and the TLS system in terms of the BMI categories (BMI ≥25 kg/m²: r=0.46; BMI <25 kg/m²: r=0.51, P=0.15).

Statistical differences across different stages and grades

The ANOVA analysis revealed significant differences in the severity index across the different ISL stages and TLS grades (P<0.001). Patients classified as stage III under the ISL staging system had significantly higher severity indices than those classified as stage II and stage I. Similarly, patients classified as grade T-5 and T-6 under the TLS system had significantly higher severity indices than those classified as grade P-1 and P-2. These results indicate that the severity index can effectively differentiate between levels of lymphedema severity as defined by both the ISL staging system and the TLS system (Figure 3).

Figure 3 The severity index across different ISL stages and TLS grades. *, P<0.05. ISL, International Society of Lymphology; TLS, Taiwan Lymphoscintigraphy Staging; SD, standard deviation.

Discussion

Our findings provide valuable insights into the correlation between the ISL staging system and the TLS system for assessing extremity lymphedema. The results revealed a strong correlation between these two systems, and excellent inter- and intra-observer reliability. This finding is particularly significant for the clinical management of lymphedema, as it supports the use of both staging systems in clinical practice. While the ISL staging system is widely recognized for its simplicity, the TLS system offers enhanced precision via quantitative imaging analysis, making it more suitable for specialized centers.

The strong correlation observed between the ISL staging system and the TLS system aligns with previous findings (5), the consistency of different stages, such as clinical presentation-based staging and image-based staging, within the same disease will provide reasonable guidance for clinical decision-making. Warren et al. (1) emphasized the need for a comprehensive staging system to guide treatment decisions and improve patient outcomes. The ISL staging system has been widely accepted in clinical settings due to its straightforward approach in classifying lymphedema severity. However, the introduction of the TLS system provides an advanced tool, particularly suited for research, as it incorporates detailed lymphoscintigraphy findings into the staging process. Unlike the purely clinical ISL staging system, the TLS system relies on ECT imaging, offering a more quantitative and objective measure of lymphedema progression.

Our findings are consistent with those of Cheng et al., who reported a significant correlation between the TLS system and other established staging methods (5). Additionally, the high reliability of the TLS system observed in our study supports the conclusions of Ho et al. (11), who showed that the TLS system can be reliably applied by clinicians, even those with varying levels of experience. Strong inter- and intra-observer reliability is critical in ensuring consistent patient evaluations, particularly in specialized settings where detailed imaging is available.

The strong agreement between the ISL staging system and the TLS system suggests that both can be used effectively, depending on the clinical environment. The simplicity of the ISL staging system makes it suitable for general healthcare settings, including those with limited resources. In primary healthcare institutions lacking ECT equipment, doctors can provide patients with initial treatment recommendations and reasonable referral services based on the convenient ISL staging system. For example, for ISL stage 1 patients with mild severity, conservative treatments such as complete decongestive therapy are often sufficient. While for ISL stage 2 or 3 patients, surgical interventions, such as lymphatic venous anastomosis (LVA) or vascularized lymph node transfer (VLNT), and comprehensive treatment are needed to achieve better outcomes. Such recommendations are often reasonable, as the correlation found between the ISL staging system and the TLS system allows doctors to roughly infer the degree of pathological progression from patients’ physical signs. However, the detailed imaging and analysis required for the TLS system make it more applicable to research-oriented or tertiary care centers where precision in staging is crucial.

These distinctions are important when considering the appropriate staging system for a given clinical scenario. Accurate TLS assessment can not only assist doctors in clinical decision making, but can also play a role in the treatment process. Finding functional lymphatic vessels is crucial to the success of LVA, even in patients with primary lymphedema. Lymphoscintigraphy is limited by the spatial resolution and static two-dimensional images of ECT; however, it still demonstrates outstanding applicability in identifying and labelling functional lymphatic vessels. According to previous research, lymphoscintigraphy and indocyanine green (ICG) lymphatic imaging employ different imaging depths; for example, in most cases, ICG lymphatic imaging only focuses on imaging the superficial layer of the collecting lymphatic channels. Conversely, lymphoscintigraphy is sufficient for the preoperative preparation for patients before LVA surgery, and enables invasive procedures, such as injection caused by repeated ICG lymphatic imaging, to be avoided. In clinical practice, lymphoscintigraphy, together with ICG lymphography and high-frequency ultrasound, has promoted the advancement of LVA technology. In patients with TLS grade P-3 and above, functional lymphatic vessels are difficult to locate; thus, VLNT may be a more suitable treatment option. At the same time, lymphoscintigraphy and ICG lymphography can be used to mark target lymph nodes and improve and track surgical outcomes (16,17).

Our study also shows the importance of standardized training for clinicians using these systems. The accuracy and consistency of staging systems rely not only on their design, but also on the ability of clinicians to apply them correctly (18). The high inter- and intra-observer reliability reported in our study indicates that with adequate training both the ISL staging system and the TLS system can be used consistently across different clinical settings.

The subgroup analyses provided additional insights into how factors, such as the cause of lymphedema and the affected limb, influence staging outcomes. For instance, the higher correlation in patients with lower-limb lymphedema compared to those with upper-limb lymphedema may be due to anatomical differences and the distinct progression patterns of lymphedema in various extremities (9). This finding highlights the need for limb-specific considerations in staging and managing lymphedema. Moreover, the differences in staging accuracy observed between primary and secondary lymphedema cases align with the findings of Szuba et al. (2), who reported that secondary lymphedema, especially post-cancer treatment, often presents with complex patterns that challenge traditional staging systems. The ability of the TLS system to incorporate detailed imaging data makes it especially valuable for capturing these complexities, particularly in secondary lymphedema. Our study also examined how factors like limb type, disease duration, and BMI affect the correlation between the ISL staging system and the TLS system. Compared to upper-limb lymphedema, lower-limb lymphedema showed a stronger correlation with both the ISL staging system and the TLS system. This is due to more noticeable and consistent changes in limb circumference in the lower limbs, which makes it easier to assess and stage lymphedema accurately. A longer disease duration (≥5 years) was generally more strongly correlated with the ISL staging system than the TLS system. The ISL staging system, which is based on visible clinical signs, aligns better with the progression of lymphedema in advanced stages, while the TLS system, which relies on imaging, may show less consistency in these cases.

In our study, the severity index was calculated by adjusting for limb circumference differences based on the BMI, provided an individualized assessment tool for the severity of lymphedema. The severity index was found to be significantly correlated with both the ISL staging system and the TLS system, underscoring its utility as a quantitative measure. The ability of the severity index to differentiate between the ISL stages and TLS classifications highlights its potential as a complementary tool in lymphedema assessment. The correlation between the severity index, ISL staging system, and TLS system show that the severity index effectively reflects the severity classifications of both staging systems. The significant differences in severity index values across different stages and grades further validate the sensitivity of this index in assessing lymphedema. This suggests that the integration of quantitative measures, such as the severity index, can enhance the accuracy and objectivity of lymphedema evaluation.

The severity index provides a practical approach to standardizing lymphedema assessment by combining clinical and anatomical parameters. Our approach is consistent with a previous study that have advocated for comprehensive assessment tools that merge clinical evaluations with quantitative indices (19). This approach offers a more nuanced understanding of lymphedema severity and can improve individualized care. Further, the severity index has some similarity with the lower extremity lymphedema (LEL) index proposed by Yamamoto et al., but the calculation process is simpler. In Imai et al.’s follow-up of patients undergoing LVA surgery, the LEL index played an important role in evaluating surgical efficacy. The severity index proposed in this study also seems to have potential in this area, but this needs to be validated in future research (17,20).

Limitations

Despite the strengths of our study, several limitations must be acknowledged. The retrospective design could have introduced potential biases, such as selection bias or which might have affected the results. In tertiary medical centers, patients who seek treatment are often late-stage patients who are very willing to undergo surgical treatment, which might have led to sample selection bias. Further research should be conducted to determine whether the ISL staging system and the TLS system also have high consistency in primary healthcare institutions that focus on conservative treatment and early disease populations. Additionally, the relatively small sample size of our study limits the generalizability of our findings to broader populations or different settings. Future studies should focus on larger, prospective cohorts to further validate our findings. For example, if validated through large-scale prospective clinical trials, the ISL staging system may replace the TLS system in certain situations to guide clinical decisions and reduce healthcare costs. At the same time, the tested severity index could also help clinical doctors make decisions and conduct follow-up based on simple and easily available patient signs, which could save costs and provide accurate and personalized assessments in the long-term follow-up process of patients. Postoperative lymphoscintigraphy can be used to confirm the re-establishment of lymphatic backflow pathways in patients undergoing VLNT surgery. This pathophysiological change may have been preceded by a significant reduction in the circumference; however, further research needs to be conducted to confirm this. Moreover, the integration of advanced imaging techniques, such as single-photon ECT/computed tomography and magnetic resonance imaging (21-23), could enhance the accuracy of staging systems like the TLS system, and provide deeper insights into the pathophysiology of lymphedema. Exploring the potential for combining clinical staging with imaging modalities to create hybrid staging systems may improve the precision and reliability of lymphedema management.

Conclusions

We found a strong correlation and high reliability between the ISL staging system and the TLS system, reinforcing their utility in clinical practice. While the ISL staging system is well suited for general clinical use, the TLS system provides more precise, research-oriented assessments. The findings support the use of both systems, depending on the clinical context and available resources, and emphasize the importance of standardized training for clinicians to ensure consistent and accurate staging. The inclusion of a severity index as a quantitative measure adds an additional layer of assessment that enhances the evaluation of lymphedema severity. Future research should address the limitations of this study and explore the integration of imaging modalities with clinical staging to further improve lymphedema management. By continuing to refine these staging systems and their application, we can improve patient outcomes and provide more personalized care for individuals with lymphedema.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://qims.amegroups.com/article/view/10.21037/qims-24-1926/rc

Funding: This study was supported by grants from the National Natural Science Foundation of China (No. 82371388) and Natural Science Foundation of Guangdong Province, China (No. 2021A1515010597).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://qims.amegroups.com/article/view/10.21037/qims-24-1926/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013) and was approved by the Institutional Review Board of The First Affiliated Hospital of Sun Yat-sen University (No. [2023]299). All patients provided written informed consent for the use of their clinical data for research purposes.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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