Long-term changes on lymphoscintigraphy and their association with clinical parameters in secondary lymphedema after breast cancer surgery

doi:10.21203/rs.3.rs-3135062/v1

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Long-term changes on lymphoscintigraphy and their association with clinical parameters in secondary lymphedema after breast cancer surgery

https://doi.org/10.21203/rs.3.rs-3135062/v1

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Purpose: To investigate long-term changes on lymphoscintigraphy and their association with clinical parameters in patients with breast cancer-related lymphedema (BCRL).

Methods: This single-center cohort study included patients with BCRL 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 into 0‒6 stages according to the Taiwan lymphoscintigraphy staging system. Clinical parameters including PEC and the lymphoscintigraphy stage at baseline and follow-up were compared and analyzed.

Results: Eighty-seven patients were included. Baseline and follow-up lymphoscintigraphies were performed at a median 7 (interquartile range [IQR]: 2‒14) and 78 (IQR: 49‒116) months after surgery, respectively. Both lymphoscintigraphy stage and PEC showed variable change during the study period, with overall increases in their severity (median PEC: 3.8–13.4%; median lymphoscintigraphy stage: 1 to 4). PEC and lymphoscintigraphy stage showed positive correlations at baseline (rho = 0.27, P=0.001) and follow-up (rho = 0.50, P<0.001). Stepwise multivariable analysis revealed cellulitis (adjusted β: 4.34; 95% confidence interval [CI]: 0.77‒7.91) and lymphoscintigraphy stage at follow-up (adjusted β: 1.47; 95% CI: 0.67‒2.28) to be independent variables for PEC at follow-up.

Conclusion: The clinical courses of BCRL and patients’ lymphoscintigraphy patterns showed diverse changes over long-term follow-up. In addition to initial lymphoscintigraphy for diagnosis, follow-up lymphoscintigraphy can be useful to visualize functional changes in the lymphatic system that may help to guide the optimal management plan in BCRL.

Breast Neoplasms

Lymphedema

Lymphoscintigraphy

Technetium phytate

Lymphatic System

Breast cancer-related lymphedema (BCRL) is a debilitating disease and often requires lifelong compression therapy [1, 2]. It can occur after sentinel lymph node biopsy or axillary lymph node dissection, with reported incidences of 6% and 20%, respectively [3]. When axillary lymph nodes are removed or damaged during surgery and radiation therapy, failure of the lymphatic drainage system can result in excessive accumulation of lymphatic materials in the interstitial space, causing a number of morbidities such as pain, chest tightness, and impaired range of motion in the affected arm, as well as long-term complications such as cellulitis or lymphangiosarcoma [4–7]. BCRL negatively affects the patient’s overall quality of life in both physical and psychological aspects.

Clinical diagnosis of BCRL is based on physical examination, and various imaging studies which are primarily focused on assessing the volume, components, or lymphatic flow of the affected limb [8]. Circumference and volume measurement of the affected limb, with comparison between the affected and non-affected limbs, are traditional volume-based approaches for indicating the presence of BCRL [9]. Component analysis includes bioelectrical impedance analysis (BIA), computed tomography (CT), dual-energy X-ray absorptiometry, and magnetic resonance imaging (MRI).[10] Lymphatic flow-based assessment includes lymphoscintigraphy and indocyanine green lymphography [10]. Although indocyanine green lymphography has gained clinical attention, it is difficult to visualize the deep lymphatic system with this approach because of its limited penetration depth [11]. Lymphoscintigraphy is a first-line diagnostic imaging tool for BCRL and allows visualization of the lymphatic flow and functional lymph node [12, 13]. Staging systems for lymphoscintigraphy that reflect the degree of lymphatic obstruction have been proposed, and the resulting stages are reported to correlate with the clinical severity of arm lymphedema [14, 15].

The clinical courses of BCRL vary, and show functional changes in the lymphatic system including loss of pre-existing lymph node function, creation of a new collateral lymphatic pathway or peripheral lymphovenous anastomosis, and development of new dermal backflow [16, 17]. As a tailored rehabilitation program may be required according to the different lymphatic drainage patterns understanding the functional changes in lymphatic circulation is important for optimal treatment [18, 19]. Lymphoscintigraphy can be used to evaluate such changes, but this modality is primarily limited to diagnostic purposes at initial work-up, and little has been reported on longitudinal changes in lymphatic circulation visualized on lymphoscintigraphy [20]. Furthermore, whether changes in lymphoscintigraphic stage are related to the clinical presentation of BCRL remains unanswered. Therefore, this study aimed to investigate the relationships between long-term changes in patterns of lymphoscintigraphy and clinical features in patients with BCRL.

Study Design, Setting, and Patients

This is a single-center retrospective study of patients with BCRL who underwent lymphoscintigraphy at our institution between March 2008 and May 2022. Patients were identified from a review of their electronic medical records performed by the authors. All identified patients were evaluated for study eligibility. The inclusion criteria were as follows: 1) secondary lymphedema after breast cancer surgery, and 2) patients who underwent baseline and follow-up lymphoscintigraphy. If follow-up lymphoscintigraphy was performed more than once, we chose the lymphoscintigraphy with a longer follow-up period or that with no intervening axillary surgery between baseline and follow-up lymphoscintigraphy. Patients were excluded from the analysis if 1) intervening axillary node dissection, 2) surgical lymphovenous anastomosis and/or lymph node transplantation were performed, or 3) bilateral lymphedema being present. The number of patients included during the study period determined the sample size of the study.

Demographic data including age, sex, body mass index (BMI), T and N stages of breast cancer, type of surgery and axillary node dissection, radiation therapy, and chemotherapy were retrospectively obtained via medical chart review. The types of radiation therapy were divided into nodal and non-nodal radiation. Other potential clinical risk factors including compliance, the type of compression (i.e., stockings, bandages), and occurrence of cellulitis were recorded. A poor compliance group was defined as those patients noted as having poor compliance in the electronic hospital record or not performing compression despite a compression-dependent status.

Evaluation of arm circumference

The circumference of the upper limb was measured at multiple locations selected from 5, 10 cm above or 5, 10, 15 cm below, the lateral epicondyle level of the elbow at each outpatient visit during follow-up, and these measurements were noted in the electronic medical record. The medical record of the outpatient visit that was closest to the time point of each lymphoscintigraphy was reviewed for this study. The percentage of excess circumference (PEC) was calculated as follows: PEC = ([circumference of the affected side – circumference of the unaffected side]/circumference of the unaffected side) × 100%. The highest PEC value among the PEC values at different arm levels was used as the representative PEC [2, 21–24].

Lymphoscintigraphy acquisition

The lymphoscintigraphy images were obtained at 1 and 2 hours after subcutaneous injection of ^99mTc-pyphate (100 nm, filtered) into the second and/or third web space of both hands with a dose of 37 MBq/0.1 mL per web space. After ^99mTc-pyphate injection, patients were instructed to exercise (clench and unclench) with rubber balls for 30 minutes to increase lymphatic flow. Anterior and posterior whole body images were acquired in a 256 × 1024 matrix with the patient in a supine position. One of three different dual-head gamma camera system devices was used: BrightView (Philips Healthcare, Best, Netherlands), Infinia (GE Healthcare, Waukesha, WI, USA), or Symbia Evo Excel (Siemens Healthineers, Erlangen, Germany), with a low-energy high-resolution parallel whole collimator at a scan speed of 13 cm/minute.

Image interpretation

Whole body lymphoscintigraphy images were independently evaluated in a blind manner by two experienced nuclear medicine physicians. In cases of discrepancy, a consensus evaluation was achieved after discussion. Each image was categorized into stages from 0‒6 according to the Taiwan lymphoscintigraphy stage proposed by Cheng et al [14]. Proximal lymph nodes were defined as axillary, infraclavicular, and supraclavicular lymph nodes, and intermediate lymph nodes were defined as collateral nodes found in the upper arm or forearm areas.

Statistical analysis

Interval and continuous variables are expressed as median with interquartile range (IQR), and dichotomous variables as number with percentage. The change in PEC and lymphoscintigraphic stage was defined as baseline value – follow-up value. The PEC and stage at baseline and follow-up lymphoscintigraphy were compared using the Wilcoxon signed-rank test. Associations between PEC, lymphoscintigraphy stage, and clinical variables were evaluated with Spearman’s rank correlation. Univariable and multivariable linear regression analyses were performed. Independent variables showing P values ≤ 0.20 in the univariable analysis were included in the stepwise multivariable analysis. Model selection was based on Akaike’s information criterion. Linear regression assumptions were checked by testing linearity, normality, homoscedasticity, and multicollinearity. The “networkD3” and “car” packages in R software (version 4.1.3 R foundation for Statistical Computing, Vienna, Austria) were used to conduct the statistical analyses.

Patient characteristics

Among the initially identified 3285 patients with BCRL who underwent lymphoscintigraphy, 150 patients underwent both baseline and follow-up lymphoscintigraphy during the study period. However, 63 patients were excluded from the analysis for the following reasons: intervening axillary node dissection (n = 6), intervening lymphovenous anastomosis and/or lymph node transplantation (n = 40), and bilateral lymphedema (n = 17). Finally, 87 patients were included in our analysis (Fig. 1). The baseline characteristics of the patients are summarized in Table 1. Information on the T and N stages of breast cancer and the number of dissected lymph nodes was not available for five patients who underwent breast cancer surgery at an outside hospital. Nodal radiation therapy was performed in 60 (69%) patients, non-nodal radiation therapy in 13 (15%), and radiation therapy with an unknown target field in five patients (6%). Baseline and follow-up lymphoscintigraphy were performed at a median of 7 (IQR: 2‒14) and 78 (IQR: 49‒116) months after surgery, respectively.

Table 1

Patient characteristics
Variables	Median (IQR) or n (%)
Age at baseline	48 (43, 55)
Female sex	87 (100%)
BMI at baseline lymphoscintigraphy (kg/m²)	23.2 (21.7, 26.2)
BMI at follow-up lymphoscintigraphy (kg/m²)	23.5 (21.3, 26.2)
T stage (Tis/1/2/3/4)^*	2/18/44/14/4 (2/21/51/16/5%)
N stage (N0/1/2/3)^*	13/32/26/11 (15/37/30/13%)
Surgery
Breast-conserving operation	40 (46%)
Mastectomy	47 (66%)
Axillary lymph node dissection	75 (86%)
Number of dissected lymph nodes^†	16 (11, 19)
Nodal radiation	60 (69%)
Chemotherapy	82 (94%)
Cellulitis	23 (26%)
Poor compliance	19 (22%)
Interval between surgery and baseline lymphoscintigraphy (mo.)	7 (2, 14)
Interval between surgery and follow-up lymphoscintigraphy (mo.)	78 (49, 116)
^{*, †}Data were not available for five and two patients, respectively.
BMI = body mass index, IQR = interquartile range.

Associations between lymphoscintigraphic stage and clinical factors

The lymphoscintigraphy stage at baseline was positively correlated with the time interval from surgery (rho = 0.26, P = 0.016; Table 2). Other clinical factors were not associated with baseline lymphoscintigraphy stage. The lymphoscintigraphy stage at follow-up was significantly associated with time interval from surgery (P = 0.001), N stage (P = 0.015), type of axillary node dissection (P = 0.023), type of radiation therapy (P = 0.003), bandage compression (P < 0.001), and cellulitis (P = 0.024) (Tables 2 and 3). In addition, change in stage between baseline and follow-up lymphoscintigraphy was significantly associated with chemotherapy (P = 0.046), bandage compression (P < 0.001), and cellulitis (P = 0.009). The associations between patient characteristics and PEC at baseline and follow-up, and its change, are presented in Supplementary Tables 1 and 2.

Table 2

Correlations between patient characteristics and lymphoscintigraphy stage at baseline, follow-up, and change in stage between baseline and follow-up.
	Baseline		Follow-up		Change
Variables	rho	P	rho	P	rho	P
Interval between surgery and lymphoscintigraphy (mo.)	0.26	0.016	0.34	0.001	NA	NA
Interval between baseline and follow-up lymphoscintigraphy (mo.)	NA	NA	NA	NA	−0.19	0.072
BMI (kg/m²)	−0.10	0.400	−0.16	0.139	NA	NA
Change in BMI between baseline and follow-up (kg/m²)	NA	NA	NA	NA	−0.09	0.416
Number of dissected lymph nodes	0.01	0.928	0.16	0.147	−0.18	0.108
N stage	0.21	0.055	0.27	0.015	−0.13	0.237
BMI = body mass index, NA = not applicable.

Table 3

Lymphoscintigraphy stage at baseline, follow-up, and change in stage between baseline and follow-up according to patient characteristics.
	Baseline		Follow-up		Change
Variables	Median (IQR)	P	Median (IQR)	P	Median (IQR)	P
ALND (vs SNB)	1 (1, 3) vs 1 (0, 2)	0.116	4 (2, 5) vs 1 (0, 4)	0.023	−1 (− 3, 0) vs 0 (− 1, 1)	0.169
Nodal (vs no/non-nodal) radiation	2 (1, 4) vs 1 (1, 2)	0.107	4 (2, 5) vs 2 (1, 4)	0.003	−1 (− 4, 0) vs 0 (− 1, 0)	0.165
Chemotherapy (vs none)	1 (1, 3) vs 2 (2, 4)	0.201	4 (2, 5) vs 2 (1, 4)	0.133	−1 (− 3, 0) vs 1 (0, 1)	0.046
Bandage compression at baseline (vs none)	2 (1, 4) vs 1 (1, 2)	0.623	NA	NA	−1 (− 4, 0) vs − 1 (− 3, 0)	0.286
Bandage compression at follow-up (vs none)	NA	NA	5 (2, 6) vs 1 (1, 4)	< 0.001	−2 (− 4, 0) vs 0 (− 1, 1)	< 0.001
Cellulitis (vs none)	2 (1, 2) vs 1 (1, 4)	0.590	4 (4, 5) vs 2 (1, 5)	0.024	−3 (− 3, − 1) vs 0 (− 3, 0)	0.009
Poor compliance (vs none)	1 (1, 4) vs 1 (1, 2)	0.764	4 (2, 5) vs 4 (1, 5)	0.368	−1 (− 3, 0) vs − 1 (− 3, 0)	0.676
ALND = axillary lymph node dissection, IQR = interquartile range, NA = not applicable, SNB = sentinel node biopsy.

Relationship of PEC with lymphoscintigraphic stage

Both PEC and lymphoscintigraphy stages changed in various manners (Fig. 2). Overall, the median PEC showed a significant increase from 3.8% (IQR: 1.6‒8.3%) at baseline to 13.4% (IQR: 7.7‒17.8%) at follow-up (P < 0.001). Lymphoscintigraphy stage also showed a significant increase at follow-up lymphoscintigraphy in comparison with baseline (median [IQR]: 1 [1–3] vs 4 [2–5], P < 0.001). The PEC and lymphoscintigraphy stage were positively correlated at both baseline (rho = 0.27, P = 0.001) and follow-up (rho = 0.50, P < 0.001) (Fig. 3a and 3b). The change in PEC and change in lymphoscintigraphy stage between baseline and follow-up also showed a positive correlation (rho = 0.30, P = 0.003; Fig. 3c). Representative images at baseline and follow-up lymphoscintigraphy are shown in Fig. 4.

Linear regression analyses of factors associated with PEC

In the univariable regression analyses, the interval between surgery and lymphoscintigraphy, nodal radiation, bandage compression, cellulitis, poor compliance, lymphoscintigraphy stage at baseline, lymphoscintigraphy stage at follow-up, and change in lymphoscintigraphy stage were significantly associated with the PEC at follow-up (Table 4). The stepwise multivariable analysis revealed that cellulitis (adjusted β = 4.34, [95% CI: 0.77‒7.91]) and lymphoscintigraphy stage at follow-up (adjusted β = 1.47 [95% CI: 0.67‒2.28]) were independent predictors of PEC at follow-up. The results of the univariable and multivariable linear regression analyses for the changes in PEC are shown in Supplementary Table 3.

Table 4

Results of univariable and multivariable linear regression analyses for PEC at follow-up lymphoscintigraphy
	Univariable		Multivariable
Variables	Crude β (95% CI)	P	Adjusted β (95% CI)	P
Interval between surgery and lymphoscintigraphy (mo.)	0.04 (0.01, 0.07)	0.024	Not included
BMI (kg/m²)	0.11 (− 0.41, 0.64)	0.673
ALND (vs SNB)	4.88 (− 0.44, 10.19)	0.072	Not included
Nodal radiation (vs none/non-nodal)	5.19 (1.4, 8.97)	0.008	Not included
Chemotherapy (vs none)	7.11 (− 1.35, 15.57)	0.098	Not included
Bandage compression at follow-up (vs not)	4.28 (0.7, 7.86)	0.020	Not included
Cellulitis (vs none)	4.97 (1.04, 8.89)	0.014	4.34 (0.77, 7.91)	0.018
Poor compliance (vs not)	5.68 (1.5, 9.86)	0.008	2.96 (− 0.57, 6.49)	0.099
Lymphoscintigraphy stage at baseline	0.98 (0.05, 1.9)	0.039	0.63 (− 0.17, 1.43)	0.121
Lymphoscintigraphy stage at follow-up	1.98 (1.19, 2.78)	< 0.001	1.47 (0.67, 2.28)	0.001
Change in lymphoscintigraphy stage	−0.84 (− 1.61, − 0.07)	0.033	Not included
ALND = axillary lymph node dissection, BMI = body mass index, CI = confidence interval, SNB = sentinel node biopsy.

In this study, we assessed the relationship between lymphoscintigraphy findings and clinical features in patients with BCRL over long-term follow-up. The clinical course of lymphedema and the lymphoscintigraphy findings showed a variety of changes over time, with a general deterioration. The lymphoscintigraphy stage was closely associated with the clinical severity of lymphedema assessed by PEC at baseline and follow-up, as well as their changes. In the multivariable analysis, lymphoscintigraphy stage was found to be an independent factor for PEC at follow-up. Our results suggest that lymphoscintigraphy is not only a useful imaging modality for initial diagnosis, but that it is also useful for monitoring functional changes in BCRL during follow-up.

Our results regarding changes in lymphoscintigraphic findings are consistent with a previous report by Szuba et al [20]. who examined serial lymphoscintigraphies at 1‒6 weeks, 1 year, and 2 years after axillary lymph node dissection in patients with breast cancer. They descriptively reported that loss of previously functional lymph nodes and appearance of new dermal backflow were commonly observed in patients with BCRL, which can be translated into change to a higher lymphoscintigraphic stage during follow-up. In addition, our study revealed that such changes in functional lymphatics visualized on lymphoscintigraphy are closely related to the changes in clinical manifestation of BCRL during follow-up. Our longer follow-up period of a median of 78 months after surgery is also a characteristic of our study differentiating it from that of Szuba et al [20]. Our findings suggests that long-term changes in the lymphatic system occur over time and can be accurately tracked by follow-up lymphoscintigraphy.

We also found that lymphoscintigraphy stage at follow-up showed significant associations with known clinical risk factors such as axillary nodal dissection, nodal radiation therapy [20] and cellulitis which is consistent with previous reports [25, 26]. However, we did not find such relationships on baseline lymphoscintigraphy. Early lymphedema can occur without lymphoscintigraphic evidence of lymphatic dysfunction [20]. Possible mechanisms of pathophysiology in BCRL include absent or insufficient collateral lymphatic circulation, lymphatic pump failure induced by lymphatic overload, and venous hypertension [27]. It is plausible that early baseline lymphoscintigraphy could not sufficiently reflect such pathophysiology, which may develop over the course of the disease. In addition to initial lymphoscintigraphy for the purpose of diagnosis, follow-up lymphoscintigraphy may also be required for patients who require comprehensive clinical and imaging assessment for optimal management.

Several staging systems for lymphoscintigraphy in patients with upper arm lymphedema have been proposed, including a previous study with ^99mTc-phytate by Cheng et al (Taiwan lymphoscintigraphy stage), and a study with ^99mTc-labeled human serum albumin by Mikami et al [14], [15]. Although both staging systems are similar, they do have some distinct features. Mikami’s classification consists of five stages, mainly differentiated by the presence and extent of dermal backflow. In the Taiwan lymphoscintigraphy staging system, lymphoscintigraphy stages are largely divided into partial obstruction (stages 1–3) and total obstruction (stage 4–6) according to the presence of proximal or intermediate lymph node uptake, with further subdivision based on the presence or extent of dermal backflow. The presence of a functional proximal lymph node on lymphoscintigraphy is known to be associated with a lower frequency of lymphedema development [28], less severe clinical manifestation, and favorable response to complex decongestive therapy [13]. We speculate that the Cheng staging system better depicted the variable clinical aspects of lymphedema in our study population who underwent lymphoscintigraphy with ^99mTc-phytate. Both staging systems lack a clear anatomical definition of proximal lymph nodes. Of note, the hierarchy of dermal backflow differs between the two staging systems: the presence of dermal backflow limited to the forearm is regarded as a higher stage than that involving the upper arm or entire arm in Mikami’s classification, whereas the presence of dermal backflow limited to the forearm is considered to represent less severe disease status than that in the entire arm according to the Taiwan lymphoscintigraphy staging system. In our study, we found that the PEC differed substantially between the partial (stage 1‒3) and total obstruction (stage 4‒6) groups, as shown in Fig. 3, whereas differences in PEC within these groups were not observed. The question of which lymphoscintigraphy staging system better depicts BCRL remains unclear, and therefore further studies on this issue are warranted.

There are several limitations to this study. First, this study is of a retrospective design. Second, there might be selection bias because our study population underwent follow-up lymphoscintigraphy, which might not have been recommended for every patient with BCRL. Third, the time interval between baseline and follow-up lymphoscintigraphy, as well as the duration from surgery to baseline lymphoscintigraphy, differed from patient to patient, and therefore an optimal timepoint for follow-up lymphoscintigraphy could not be derived from our study. In future prospective studies, a more regular follow-up period should be set. Fourth, the type of treatment varied because patients received individualized optimal management of lymphedema. Although we excluded patients who underwent surgical intervention, there still remained some differences within the conservative treatment. Finally, our results may not be applicable to lymphoscintigraphy with different tracers and acquisition protocols, which can substantially affect its interpretation [29].

In conclusion, the clinical course of BCRL, its pattern on lymphoscintigraphy, and its clinical features varied over time. In addition to initial lymphoscintigraphy for diagnostic purposes, follow-up lymphoscintigraphy can objectify and visualize diverse changes in the functioning of the lymphatic system, which may help categorize the clinical severity of lymphedema and guide the optimal management plan in patients with BCRL.

BCRL breast cancer-related lymphedema

BIA bioelectrical impedance analysis

CI confidence interval

CT computed tomography

IQR interquartile range

IRB institutional review board

MRI magnetic resonance imaging

PEC percentage of excessive circumference

Author contributions: The authors have contributed to the paper as follows: Garam Hong, Koeun Lee, Sangwon Han, and Jae Yong Jeon contributed to study conceptualization, data acquisition, data analysis, data interpretation, writing, and editing of the manuscript. All authors have read and approved the final manuscript.

Data Availability: The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Disclosure of potential conflicts of interest: This research was supported by a grant from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (grant number: HR18C0016). The authors have no potential conflicts of interest.

Acknowledgments: None

Ethics approval: Institutional Review Board of Seoul Asan medical center approved this study (IRB No. 2022-0869) and waived the need to obtain informed consent because of its retrospective nature. This study was conducted in accordance with the Declaration of Helsinki and our institutional guidelines.

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Long-term changes on lymphoscintigraphy and their association with clinical parameters in secondary lymphedema after breast cancer surgery

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Abstract

Figures

Introduction

Materials and Methods

Study Design, Setting, and Patients

Evaluation of arm circumference

Lymphoscintigraphy acquisition

Image interpretation

Statistical analysis

Results

Patient characteristics

Associations between lymphoscintigraphic stage and clinical factors

Relationship of PEC with lymphoscintigraphic stage

Linear regression analyses of factors associated with PEC

Discussion

Abbreviations

Declarations

References

Status:

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