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 (P1–5); on the midsternum at the level of the first/forth rib junctions (P1–2), 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 (P1–2), 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.
