Indocyanine Green Lymphography for Evaluation of Breast Lymphedema Secondary to Breast Cancer Treatments

Abstract

Background Although breast lymphedema (BL) significantly deteriorates quality of life (QOL) of breast cancer survivors, little is known and pathophysiological severity staging system is yet reported. This study aimed to evaluate usefulness of a novel BL severity staging system based on indocyanine green (ICG) lymphography findings.

Methods Breast cancer survivors with breast symptoms who underwent breast ICG lymphography were included. Breast ICG lymphography stage was determined based on visibility of linear pattern and extension of dermal backflow patterns. Prevalence of breast symptoms and lymphedema QOL score (LeQOLiS) was compared according to the stage.

Results Thirty-seven patients were included. Breast ICG lymphography stage included stage 0 in 11 (29.7%) cases, stage I in 3 (8.1%) cases, stage II in 11 (29.7%) cases, stage III in 6 (16.2%) cases, stage IV in 4 (10.8%) cases, and stage V in 2 (5.4%) cases. Higher ICG stages were associated with more frequent prevalence of breast swelling (p = 0.020), breast pain (p = 0.238), and breast cellulitis (p = 0.024), and with higher LeQOLiS (p < 0.001).

Conclusion ICG lymphography allows clear visualization of superficial lymph circulation in the breast. Higher breast ICG lymphography stages are associated with more frequent prevalence of BL-related symptoms and worse QOL.

Keywords

lymphedema - indocyanine green - breast cancer - supermicrosurgery - anastomosis

Quality of life (QOL) of cancer survivors is becoming a major public health issue to be addressed, as prognosis of cancer patients is improved with advancement of multidisciplinary cancer treatments.[1] [2] [3] Secondary lymphedema is one of the most significant complications after breast cancer treatments, since lymphedema is progressive and intractable in nature.[3] [4] [5] [6] [7] Once developed, breast cancer treatment–related lymphedema (BCRL) basically requires life-long conservative treatments such as compression therapy and manual lymph drainage.[3] [4] [7] BCRL includes upper extremity lymphedema (UEL) and breast lymphedema (BL), as the axillary lymph nodes drain lymph from the upper extremity and the breast.[8] [9] [10] [11] [12] Although numerous clinical studies focus on UEL, there have been a few studies focusing on BL.[9] [10] [12] [13]

BL is obstructive lymphedema due to axillary lymph node biopsy/dissection and/or irradiation.[9] [10] [11] [12] [13] Clinical manifestations include swelling or tension of the breast and cellulitis-related symptoms as seen in UEL.[10] [12] [13] Painful swelling and cellulitis are major reasons for patients to seek for specific treatment of BL, significantly affecting QOL of breast cancer survivors.[9] [10] [11] [13] Although some breast cancer survivors notice their symptoms due to BL, most BL cases are considered subclinical without subjective symptoms.[4] [12] [14] Even in subclinical BL cases, serious long-term sequela can occur such as breast angiosarcoma called Stewart–Treves syndrome.[2] [14] [15] Therefore, appropriate evaluation and intervention is important to improve BL patients' QOL and prevent lethal sequelae.[3] [9] [11] [13] Diagnosis is usually done based on history taking and typical clinical findings of lymphedema, and conservative and surgical treatments are performed as in UEL.[10] [11] [13] However, diagnosis and severity evaluation are more challenging than UEL, as the breast is small, making it difficult to apply lymphoscintigraphy, a gold standard of lymph flow imaging.[2] [10] [11] [16] [17] Lymph flow imaging is critical for lymphedema evaluation, since prognosis and therapeutic response of lymphedema are closely related to lymph circulation.[10] [18] [19] [20] [21] Pathophysiological severity staging system based on lymph circulation is warranted for evaluation of BL.

Indocyanine green (ICG) lymphography has been reported to be useful for pathophysiological evaluation of lymphedema in various regions such as the upper extremity, lower extremity, head and neck, and genitalia.[4] [16] [17] [19] [20] [21] [22] [23] [24] [25] Pathophysiological severity staging systems based on ICG lymphography findings have been reported to be useful for prediction of lymph vessels' conditions and therapeutic efficacy of conservative and surgical treatments.[6] [19] [20] [21] [26] However, there has been no report of severity staging system based on ICG lymphography findings. This study aimed to develop a novel ICG lymphography severity staging system for evaluation of BL.

Patients and Methods

Breast cancer survivors with subjective symptoms of the breast who underwent breast ICG lymphography from May 2014 to June 2017 were included in this study. Patients who underwent autologous tissue breast reconstruction or BL treatments were excluded from the study. Medical records of the patients were reviewed to collect patient characteristics and ICG lymphography findings. According to previously published ICG lymphography stages for various parts of lymphedema other than BL, breast ICG lymphography stage was developed based on lymphography findings, and its feasibility was evaluated.[4] [16] [17] [22] [23]

Breast ICG lymphography was performed as previously reported.[11] [27] [28] ICG of 0.1 mL (diagnogreen 0.25%; Daiichi Sankyo, Tokyo, Japan) was intradermally injected at five points (P_1–5); on the midsternum at the level of the first/forth rib junctions (P_1–2), at the xiphoid process (P₃), at the intersection of the midclavicle line and the costal arch (P₄), and at the intersection of the anterior axillary line and the horizontal line of the P₄ (P₅; [Fig. 1]). ICG lymphography images were obtained using an infrared camera system (Photodynamic Eye [PDE]; Hamamatsu Photonics K.K., Hamamatsu, Japan), and lymphographic findings were marked on the skin according to previously reported typical ICG lymphography findings; Linear, Splash, Stardust, and Diffuse pattern ([Fig. 2]).[4] [22] Linear pattern is marked at an early transient phase immediately after ICG injection. Dermal backflow patterns of splash, stardust, or diffuse pattern were marked at a late plateau phase 2 hours after ICG injection. Breast ICG lymphography stage was developed based on visibility of linear pattern and extension of dermal backflow patterns.

Fig. 1 ICG injection sites for breast ICG lymphography; on the mid-sternum at the level of the first/forth rib junctions (P_1–2), at the xiphoid process (P₃), at the intersection of the mid-clavicle line and the costal arch (P₄), and at the intersection of the anterior axillary line and the horizontal line of the P₄ (P₅). ICG, indocyanine green.

Fig. 2 Characteristic ICG lymphographic findings. ICG, indocyanine green.

Collected data included age, body mass index (BMI), laterality/treatments of breast cancer, duration between breast cancer treatments and ICG lymphography, comorbidity of UEL, subjective symptoms of BL, lymphedema QOL score (LeQOLiS), and breast ICG lymphography stage. LeQOLiS consists of 10 questionnaires regarding subjective lymphedematous symptoms ([Table 1]); a summation of each score (0, least severe; 100, most severe) was used to quantify the subjective symptoms related to BL.[29] Prevalence of each subjective symptom and LeQOLiS were compared according to the breast ICG lymphography stage. Plus–minus value expressed mean ± standard deviation. Chi-square test and analysis of variance were used for statistical analyses. Statistical significance was defined as p < 0.05. This retrospective observational study was conducted under ethical institutional review boards' approved protocol (TMBH16–20, NCGM-G-003463–00), and all patients gave written informed consent prior to the study.

Table 1 LeQOLiS based on questionnaires related to breast lymphedema

Questionnaire	Score
Distension	0–10[a]
Heaviness	0–10[a]
Pain	0–10[a]
Dysesthesia	0–10[a]
Appearance distortion	0–10[a]
Motor dysfunction	0–10[a]
Limitations in daily activity	0–10[a]
Influence on social activity	0–10[a]
Distress by conservative treatment	0–10[a]
Overall dissatisfaction caused by lymphedema	0–10[a]
LeQOLiS = summation of scores	0–100 [b]

Abbreviation: LeQOLiS, lymphedema quality of life score.

^a 0, least severe; 10, most severe.

^b 0, least severe; 100, most severe.

Results

Thirty-seven patients were included in the study. All patients had undergone unilateral breast cancer treatments; there was no bilateral breast cancer case. Patient's age ranged from 29 to 80 years (average: 50.7 years), and BMI from 17.9 to 31.1 kg/m² (average: 23.43 kg/m²). Laterality of breast cancer was left in 20 (54.1%) cases and right in 17 (45.9%) cases. Breast cancer treatments included total mastectomy in 24 (64.9%) cases, partial mastectomy in 13 (35.1%) cases, axillary lymph node dissection in 16 (43.2%) cases, sentinel lymph node biopsy in 21 (56.8%) cases, chemotherapy in 29 (78.4%) cases, and radiotherapy in 17 (45.9%) cases. Thirty-one (83.8%) patients were associated with UEL. Subjective symptoms of the breast included tension in 20 (54.1%) cases, swelling in 15 (40.5%) cases, dysesthesia in 24 (64.9%) cases, pain in 7 (18.9%) cases, and cellulitis episodes in 2 (5.4%) cases. LeQOLiS ranged from 0 to 33 (average: 6.1).

Breast ICG lymphography stage was determined based on visibility of linear pattern and extension of dermal backflow patterns. Extension of dermal backflow was evaluated by counting regions showing dermal backflow. The region of interest was divided into three regions as follows: (1) axillary region, the region lateral to the anterior axillary line; (2) mammary region, the anterior chest region above the inframammary fold; and (3) extramammary region, the anterior chest region below the inframammary fold ([Fig. 3]). Breast ICG lymphography stage included stages 0, I, II, III, IV, and V ([Table 2] and [Fig. 4]); in ICG stage 0, only linear pattern is observed without any dermal backflow pattern, representing normal lymph circulation; in ICG stage I, linear and splash patterns are observed; in ICG stage II, stardust/diffuse pattern was observed in one region with linear pattern; in ICG stage III, stardust/diffuse pattern was observed in two regions with linear pattern; in ICG stage IV, stardust/diffuse pattern was observed in three regions with linear pattern; and in ICG stage V, only stardust/diffuse pattern was observed without linear pattern. Breast ICG lymphography stage included stage 0 in 11 (29.7%) cases, stage I in 3 (8.1%) cases, stage II in 11 (29.7%) cases, stage III in 6 (16.2%) cases, stage IV in 4 (10.8%) cases, and stage V in 2 (5.4%) cases.

Fig. 3 Region classification for breast ICG lymphography; axillary region (A), mammary region (B), and extramammary region (C). ICG, indocyanine green.

Table 2 Breast ICG lymphography stage

ICG stage	ICG lymphography findings
Stage 0	Linear pattern only[a]
Stage I	Linear pattern + splash pattern
Stage II	Linear pattern + stardust/diffuse pattern (one region)[b]
Stage III	Linear pattern + stardust/diffuse pattern (two regions)[b]
Stage IV	Linear pattern + stardust/diffuse pattern (three regions)[b]
Stage V	Stardust/diffuse pattern only[c]

Abbreviation: ICG, indocyanine green.

^a Dermal backflow pattern is not seen.

^b Divided into three regions; the axillary region, the mammary region, and the extramammary region.

^c Linear pattern is not seen.

Fig. 4 Breast ICG lymphography stage. Dotted lines denote linear pattern, scattered tortuous lines Splash pattern, and circled areas stardust/diffuse pattern. ICG, indocyanine green.

Positive rate of breast tension was 4 of 11 (36.4%) in ICG stage 0, 2 of 3 (66.7%) in ICG stage I, 5 of 11 (45.5%) in ICG stage II, 4 of 6 (66.7%) in ICG stage III, 3 of 4 (75.0%) in ICG stage IV, and 2 of 2 (100%) in ICG stage V ([Fig. 5A]); there was no statistically significant difference between ICG stages (p = 0.454). Positive rate of breast swelling was 2 of 11 (18.2%) in ICG stage 0, 0 of 3 (0%) in ICG stage I, 4 of 11 (36.4%) in ICG stage II, 3 of 6 (50.0%) in ICG stage III, 4 of 4 (100%) in ICG stage IV, and 2 to 2 (100%) in ICG stage V ([Fig. 5B]); there was a statistically significant difference between ICG stages (p = 0.020). Positive rate of breast dysesthesia was 6 of 11 (54.5%) in ICG stage 0, 1 of 3 (33.3%) in ICG stage I, 8 of 11 (72.7%) in ICG stage II, 5 of 6 (83.3%) in ICG stage III, 4 of 4 (100%) in ICG stage IV, and 9 of 2 (0%) in ICG stage V ([Fig. 5C]); there was no statistically significant difference between ICG stages (p = 0.114). Positive rate of breast pain was 0 of 11 (0%) in ICG stage 0, 1 of 3 (33.3%) in ICG stage I, 2 of 11 (18.2%) in ICG stage II, 1 of 6 (16.7%) in ICG stage III, 2 of 4 (50.0%) in ICG stage IV, and 2 of 2 (50.0%) in ICG stage V ([Fig. 5D]); there was a statistically significant difference between ICG stages (p = 0.238). Positive rate of breast cellulitis was 0 of 11 (0%) in ICG stage 0, 0 of 3 (0%) in ICG stage I, 0 of 11 (0%) in ICG stage II, 0 of 6 (0%) in ICG stage III, 1 of 4 (25.0%) in ICG stage IV, and 1 of 2 (50.0%) in ICG stage V ([Fig. 5E]); there was a statistically significant difference between ICG stages (p = 0.024).

Fig. 5 Prevalence of breast symptoms and breast ICG lymphography stage; breast tension (A), breast swelling (B), breast dysesthesia (C), breast pain (D), and breast cellulitis (E). ICG, indocyanine green.

There was a significant difference in LeQOLiS between ICG stages (2.3 ± 3.8 in stage 0, 2.0 ± 1.0 in stage I, 3.4 ± 2.8 in stage II, 5.0 ± 5.7 in stage III, 21.0 ± 8.5 in stage IV, and 22.0 ± 4.2 in stage V; p < 0.001; [Fig. 6]).

Fig. 6 LeQOLiS and breast ICG lymphography stage. ICG, indocyanine green; LeQOLiS, lymphedema quality of life score.

Discussion

This study revealed that higher breast ICG lymphography stages were associated with higher LeQOLiS, representing good relationship between ICG stage and QOL. To our knowledge, this is the first study reporting pathophysiological severity staging system for BL based on lymph circulation with statistically significant relationship to QOL in BL patients. There were statistically significant differences in prevalence of breast swelling and cellulitis according to ICG stage, whereas there was no statistically significant differences in breast tension, dysesthesia, or pain, suggesting that breast swelling and cellulitis are good clinical indicators suspecting BL. Breast tension, dysesthesia, or pain may be caused by breast cancer surgery itself and are not specific to BL.[2] [3] [11] [12] [13] Diagnosis of BL should not be done solely based on subjective symptoms, and lymph flow imaging study is warranted for BL diagnosis.[10] [11] [12] [13] [28] [30]

Although lymphoscintigraphy is a gold standard for lymph flow imaging, its images are obscure, making it difficult to evaluate lymph circulation in a small region such as the breast.[3] [8] [10] [13] [16] [17] [18] Previous studies have revealed that ICG lymphography has higher sensitivity and specificity to detect abnormal lymph circulation in extremity lymphedema than lymphoscintigraphy.[14] [23] [31] [32] Lymph circulation was intact in 11 (29.7%) cases among the 37 breast cancer survivors with breast symptoms in this study cohort. As these symptoms are common after breast surgery, especially after axillary lymph node dissection, a considerable number of patients with some breast symptoms are not associated with BL.[2] [12] [13] Since lymphedema is defined as an edematous disease caused by abnormal lymph circulation, only patients with ICG stages I to V should be diagnosed as BL.[4] [14] [17] [23] [33] There would also be asymptomatic breast lymphedema cases in breast cancer survivors in which ICG lymphography shows abnormal findings. Further studies are required to clarify prevalence and risk factors of breast lymphedema in cancer survivors.

Previous studies have clarified that lymphedematous lesions with abnormal lymph circulation on ICG lymphography are associated with poor prognosis which can be improved by appropriate interventions.[4] [17] [23] [26] [28] [34] With progression of lymphedema, lymphedematous lesions are likely to be associated with dysmorphia, limitations in daily activity, higher frequency of cellulitis, and long-term sequela of angiosarcoma development.[3] [14] [15] [19] [20] [21] [30] [33] [35] Once breast lymphedema is diagnosed, conservative treatments, such as manual lymph drainage with or without surgical interventions, should be considered. When conservative treatments fail to control breast lymphedema, especially when breast lymphedema is associated with cellulitis, surgical interventions are considered. Physiologic or reconstructive lymphatic surgeries, such as lymphovenous shunt and vascularized lymph node transfer, improve abnormal lymph circulation, and prevent progression of lymphedema.[6] [11] [18] [26] [27] [28] [30] [34] [35] Although all previous studies are on extremity lymphedema cases and no study reports on BL cases, similar findings can be expected in BL cases; early diagnosis of BL with ICG lymphography and appropriate interventions may improve prognosis of BL.[6] [14] [23] [26] [28] [30] [36] [37]

Advantages of ICG lymphography include clear visualization of superficial lymph flows without a risk of ionized radiation exposure.[4] [6] [16] [17] [22] [28] [30] [38] As the breast is a small region which can hardly be assessed by a gold standard of lymphoscintigraphy, ICG lymphography is considered an optimal modality to assess pathophysiological conditions of BL.[10] [16] [17] [31] Clear lymph flow visualization is useful also for navigation of BL treatments.[9] [10] [19] [21] [26] [28] [39] [40] Manual lymph drainage can be optimized based on ICG lymphography findings, and lymphovenous shunt operations can be done via a small incision under ICG lymphography navigation.[26] [30] [39] [40]

Disadvantages of ICG lymphography are that ICG injection has a risk of allergy or bronchial asthma exacerbation, that a near-infrared camera is required for enhancement, and that deep lymph circulation cannot be visualized.[4] [16] [17] [22] [28] [31] [32] As ICG contains iodine, ICG lymphography cannot be performed on a patient with past history of iodine allergy or bronchial asthma.[4] [22] [39] It is necessary to prepare a near-infrared camera for ICG lymphography before clinical application.[4] [10] [16] [17] [23] Since ICG lymphography can visualize lymph flows up to 2 cm from the skin surface, deep lymph flows cannot be directly assessed.[10] [16] [17] [24] [30] Deep lymph flow visualization using magnetic resonance lymphography or other imaging studies should be combined for comprehensive assessment of lymph circulation.[4] [16] [17] [22] [30] [31] [32]

Limitations

Limitations of the study include the small number of patients with a single ethnic group, retrospective observational nature of the study, and that direct relationship between ICG lymphography findings and clinical outcomes has yet been confirmed. Although the study demonstrated relationship between higher ICG stage and worse QOL, long-term clinical outcomes of BL with abnormal lymph circulation on ICG lymphography was not assessed. Appropriate interventions according to ICG lymphography findings, as reported in extremity lymphedema cases, have yet been clarified to improve clinical outcomes of BL.[6] [19] [21] [26] [27] [28] [30] Further prospective studies are required to clarify natural course and risk factors of breast lymphedema and to confirm usefulness of ICG lymphography for BL diagnosis and pathophysiological severity evaluation to improve the prognosis.

Conclusion

ICG lymphography allows clear visualization of superficial lymph circulation in the breast. Higher breast ICG lymphography stages are associated with more frequent prevalence of BL-related symptoms and worse QOL.

Conflicts of Interest

None declared.

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Publication History

Received: 03 August 2021

Accepted: 26 December 2021

Article published online:
08 February 2022