Alteration of Blood Circulation in the Upper Limb Before and After Surgery for Breast Cancer Associated with Axillary Lymph Node Dissection or Sentinel Lymph Node Biopsy

Abstract

Background:

This aim of this study was to assess and compare arterial and venous circulation in women with axillary lymph node dissection (ALND) and sentinel lymph node biopsy (SLNB) before and after breast cancer surgery.

Methods and Results:

Fifty-two women took part in the study, divided into three groups: those undergoing ALND at levels I, II, and III (ALNDG), with mean age of 56.29 ± 10.85 years old; those undergoing sentinel lymph node biopsy (SLNBG), with mean age of 57.7 ± 7.07 years old; and controls without diagnosis of breast cancer (CG), with mean age of 53.92 ± 8.85 years old. Maximum venous and arterial flow velocities in upper limbs were assessed before and after surgical treatment for breast cancer by means of Doppler ultrasonography (Nicolet Vascular Versalab SE^®). Data normality was assessed by using the Shapiro–Wilk's test, with normally distributed variables being analyzed with analysis of variance (ANOVA) and post hoc Tukey's test or t-test. For variables with non-normal distribution, Kruskal–Wallis' test and post hoc Dunn's test were used at p < 0.05. There was significant difference in the maximum blood flow velocities, both venous (ALNDG) and arterial (SLNBG).

Conclusion:

The results suggest that ALND and SLNB can interfere with the upper limp blood circulation.

Introduction

Aprojection of incidence and cancer deaths for the years 2020 and 2030, based on changing demographics, incidence, and mortality rates, shows breast cancer as one of the leading diagnoses of this period; however, advances in screening, prevention, and treatment can change this perspective.¹ Overall survival after 5 years is 83.7% and 79.8% with and without postmastectomy radiotherapy and in 10 years this decreases to 67.4% and 59.2%.²

Surgical treatment for breast cancer, allied with axillary lymph node dissection (ALND) and adjunctive treatments, is frequently thought to unchain or aggravate vascular morbidities.³ The surgical modality is established depending on the disease stage, including planning of adjunctive therapy and total ALND.⁴ However, the need for this procedure has been questioned, mainly regarding the related sequels.

The sentinel lymph node biopsy (SLNB) has been adopted as a less aggressive procedure to reduce the morbidities resulting from breast cancer treatment. This procedure before neoadjuvant chemotherapy seems to be successful and safe so that ALND can safely be omitted.⁵ However, it is not completely innocuous, also being associated with the development of lymphedema at a low scale, however.⁶

The main functional morbidities affecting the upper limb homolateral to the breast cancer surgery, allied with either ALND or SLNB, and having an impact on daily life activities are the following: chronic edema or lymphedema, pain, movement limitation, sensory disturbances, seroma, and infection.^7,8

Historically, the development of lymphedema is associated with changes in both lymphatic flow resulting from breast cancer treatment and blood circulation (arterial and venous), in addition to individual predisposition.^9–11

Studies^10,12 point to the existence of an anterior blood flow predisposition related to the emergence of secondary lymphedema after surgery for breast cancer treatment, but this supposition has not yet been totally established.

Because alterations in the blood flow of upper limbs before and after surgical treatment for cancer have not been clarified yet, the hypothesis raised by this study is based on the possibility of occurrence of changes in peripheral arterial and venous circulation before and after surgery involving either ALND or SLNB.

Materials and Methods

Patients and procedures

Women aged 40–60 years old, who would undergo breast cancer surgery, either mastectomy or lumpectomy, involving ALND or SLNB, were invited to participate in the study, as well as those in the same age range without history of cancer. All the subjects practiced no physical activity regularly, per criteria set by the International Physical Activity Questionnaire (IPAQ).¹³

A total of 52 women were divided into three homogeneous groups determined by sample calculation as follows: axillary lymph node dissection group (ALNDG), patients with mean age of 56.87 ± 10.52 years old undergoing ALND at levels I, II, and III; sentinel lymph node biopsy group (SLNBG), patients with mean age of 57.7 ± 7.07 years old undergoing SLNB; and control group (CG), women without the disease.

Women who underwent bilateral ALND were excluded from this study, once the contralateral side was analyzed comparatively; also women with history of breast radiotherapy, because studies have shown formation of coagulative necrosis in the affected area,^14–16 women with obesity equal to or greater than Grade II were excluded, pregnant or diagnosed with metastatic disease, severe lesions in muscle, tendon and/or joint of the limb homolateral to surgery, skin affections (e.g., ulcers and erysipelas), shoulder movement limitation, rheumatic–orthopedic diseases, or any peripheral circulatory dysfunction that might interfere with the upper limb function.

The procedures used in this study were approved by the Human Research Ethics Committee of the University of São Paulo (São Paulo, Brazil) and informed consent was obtained from all patients.

The subjects were initially subjected to clinical evaluation in which data on blood pressure, circumferential measurements, and volumetry of upper limb were collected, including observation of the main lymphedema-related symptoms (e.g., presence of pain, limb discomfort, and skin trophic changes), habits, and physical examinations. The following data were obtained from medical records: medication in use (dosage, name, and frequency), weight and height for calculation of body mass index (BMI), surgery-related side effects, length and date of surgery, date of beginning of chemotherapy, and amount of chemotherapy cycles.

Women undergoing ALND or SLNB had their blood flow (arterial and venous) evaluated before and ∼21 days after the surgical procedure.¹⁷ Control women had only one evaluation to compare the amount of blood flow between the groups.

The perimetric evaluation was performed to calculate the volumetry of upper limbs agreeing with the criteria established by Sander et al.¹⁸ Lymphedema was considered when the volume difference between the limbs was >200 cm³.¹⁹

A portable spectral continuous-wave Doppler ultrasound (Nicolet Vascular Versalab SE^®, Madison) operating at 8 MHz was used for evaluation of both blood flow and ankle–arm index. The spectral analysis allows the blood flow profile to be observed, including velocity (cm/s), direction, and mean values, so that the quality of the blood flow can be recorded.

The degree of arterial impairment was evaluated by means of the ankle–brachial index (ABI),²⁰ aiming to identify the presence of arterial dysfunction. It was assessed in the preoperative period in accordance with the criteria already established in the literature.^21–23 Values of ABI >0.9 and <1.4 were considered normal, whereas values <0.9 (compatible to peripheral arterial disease) and >1.4 were thought to be suggestive of changes in the peripheral arterial circulation, possibly arteriosclerosis.²²

Regarding the evaluation of blood flow in brachial veins, the patients rested in supine position for 5 minutes at a controlled temperature of 25°C.²⁴

Assessment of the velocity of arterial and venous blood flow was performed in the antecubital fossa, with the upper limb relaxed in slight shoulder position of abduction and forearm in supine position.²⁵ The transductor was attached to the skin with sterile hydro-soluble gel as interceptor and positioned at 45° in relation to the blood vessel to be assessed. This procedure was repeated three times at 1-minute interval. The site for assessment of the blood vessel was confirmed by observing the sound signals and spectral image produced by the Doppler device.

Statistics

The sample was calculated based on a study conducted by Matheus and Guirro,⁹ with statistical power of 80% and alpha error of 0.05. The software used was the StateMate 2 (GraphPad Software^® v 2.0), resulting in 15 subjects per group.

The variables “age,” “BMI,” “ABI,” “skin temperature,” and “surgery length” had normal distribution, with analysis of variance (ANOVA) test and then post hoc Tukey's test or t-test being applied. Regarding the variable “maximum blood flow velocity,” which had normal distribution, the Kruskal–Wallis and post hoc Dunn's tests were used. A critical level of 5% (p < 0.05) was set for all calculations. Data processing was performed by using the software BioEstat^® 5.3.

Results

The anthropometric characteristics and length of surgery of the patients participating in the study are listed in Table 1. No significant difference was found between the general characteristics of the patients regarding age (p = 0.50), BMI (p = 0.79), or length of surgery (p = 0.63).

Table 1.

Volunteer Characteristics

Group	No. of individuals involved	Age (years)	BMI ( kg/m²)	Surgery time (months)
CG	17	53.82 ± 7.87	29.34 ± 6.14	0
ALNDG	23	56.87 ± 10.52	29.84 ± 6.01	1.75 ± 0.69
SLNBG	12	57.17 ± 7.07	28.44 ± 3.94	1.77 ± 0.68

p < 0.05; no significant difference was found.

ALNDG, axillary lymph node dissection group; BMI, body mass index; CG, control group; SLNBG, sentinel lymph node biopsy group.

The values of ABI showed that the patients had no arterial impairment by chronic arterial disease (>0.9 and <1.4 mmHg). The difference in volume (cm³) does not demonstrate any evidence of lymphedema (Table 2).

Table 2.

Characteristics of the Groups Regarding Ankle–Brachial Index and Volume Difference (cm³)

			Volume
Group	No. of individuals involved	ABI (mmHg)	Before surgery	After surgery
CG	17	1.03 ± 0.07	0.120 ± 0.040	0.120 ± 0.040
ALNDG	23	1.06 ± 0.10	0.018 ± 0.071	0.024 ± 0.087
SLNBG	12	1.03 ± 0.08	0.007 ± 0.059	0.037 ± 0.133

p < 0.05; no significant difference was found.

ABI, ankle–brachial index.

Data on dominance limb between the groups involved showed that 100% of the patients who underwent surgical procedure were right handed, and the percentage between operated side and dominance is ∼50% (Table 3).

Table 3.

Dominance Limb and Operated Side in the Volunteers

		Dominant limb		Surgical side
Group	No. of individuals involved	R (%)	L (%)	R (%)	L (%)
CG	17	88.24	11.76	0	0
ALNDG	23	100	0	43.48	56.52
SLNBG	12	100	0	58.33	41.67

p < 0.05; no significant difference was found.

R, right; L, left.

Inter-rater analysis of ALNDG regarding maximum arterial and venous blood flow velocities before and after surgery, with surgical procedure in the dominant limb (GS-D) and nondominant limb (GS-ND), showed that there is no statistical difference in any analyzed variable, a fact that allows us to study mixed groups regarding limb dominance without interfering with the analyses (Table 4).

Table 4.

Influence of Dominance Limb in the Median Values (First and Third Quartiles) of Maximum Blood Flow Velocity of Brachial Artery and Vein in the Limbs Homolateral and Contralateral to the Surgery in the Axillary Lymph Node Dissection Group

ALNDG	Vein before surgery homo	Vein before surgery contra	Vein postsurgery contra	Vein postsurgery contra	Artery before surgery homo	Artery before surgery contra	Artery postsurgery contra	Artery postsurgery contra
GS-D	21.5 (16–45.75)	27 (16.25–51.75)	15 (12.75–21)	16.5 (11.15–21)	85 (80–122.25)	84 (64.75–85)	73.5 (57.75–85)	85 (67.25–85)
GS-ND	17 (15–36)	28 (15.5–67)	17 (12–23)	17 (12–22.5)	85 (83.5–89.5)	85 (79–85)	85 (70.5–101)	85 (74–105.5)

p < 0.05; no significant difference was found.

Contra, contralateral; GS-D, group undergoing surgical procedure in the dominant limb; GS-ND, group underlying surgical procedure in the nondominant limb before and after surgery; homo, homolateral.

The SLNBG presented a significant reduction of blood flow velocity of brachial vein when compared before and after surgery in the homolateral and contralateral limbs. There was a significant reduction of blood flow velocity of brachial artery in SLNBG when compared before and after surgery in the homolateral limb (Table 5).

Table 5.

Median Values (First and Third Quartiles) of Maximum Blood Flow Velocity of Brachial Artery and Vein in the Limbs Homolateral and Contralateral to the Surgery

		Homolateral		Contralateral
		Brachial vein	Brachial artery	Brachial vein	Brachial artery
CG		13.5 (12–20.75)	85 (62.5–105)	—	—
ALNDG	Before surgery	19 (15–45)^a,b	85 (83–109)	27 (16–64)^b,c	85 (71–85)
ALNDG	After surgery	17 (12–23)	85 (65–85)	17 (11–22)	85 (68–94)
SLNBG	Before surgery	18 (15–21)	102 (85–115.5)^d,e	17 (14.75–24.25)	104.5 (85–123.75)^e,f
SLNBG	After surgery	15 (11.75–23)	80 (53.25–85)	16.5 (11.75–23.25)	85 (75.75–111.5)

p < 0.05 × vein after surgery homolateral ALNDG.

p < 0.05 × vein CG.

p < 0.05 × vein after surgery contralateral ALNDG.

p < 0.05 × artery after surgery homolateral SLNBG.

p < 0.05 × artery CG.

p < 0.05 × artery before surgery contralateral ALNDG.

The blood flow velocity was significantly lower in the CG than before surgery of the ALNDG in the brachial vein, and in the brachial artery when compared with the SLNBG. The SLNBG presented a higher significant value of blood flow velocity in brachial artery when compared with the ALNDG in limb contralateral before surgery (Table 5).

Conclusion

Surgical procedures involving ALND or SLNB are possibly associated with comorbidities of the breast cancer treatment.²⁶

Lymphedema is a comorbidity with etiology multifactorial and has not yet been fully clarified.²⁴ Several risk factors are related to its development, with obesity,^4,28 ALND, SLNB,²⁹ radiotherapy, infection, and ethnic group being the most important factors.³⁰ Obesity and diabetes are considered a risk factor for vascular dysfunctions^31,32; to ensure that it does not interfere in the results, obese women were excluded from this study.

The relationship between incidence of lymphedema after breast cancer treatment and surgical procedures is reported to be about 8% for SLNB and 14% for ALND, whereas 65% are associated with mastectomy, ALND, and radiotherapy.³³

The involvement of blood circulation in the development of lymphedema in upper limbs as a result of surgical breast cancer treatment has been reported.^7,34 However, the contribution of possible dysfunctions of this system as a predisposing factor before treatment, as well as the role played by ALND and SLNB within this context, has not been established, and there are a few studies investigating changes in the lymphatic circulation after these two surgical procedures,³⁵ whereas there is no study addressing modifications in the blood circulation after these same interventions, which reinforces the importance of an investigation on this issue.

Relevant alterations in the lymphatic circulation before surgery has been reported.³¹ Studies have correlated blood and lymphatic dysfunctions with lymphedema, indicating them as a possible factor triggering the so-called lymphovenous derivation,^11,12,36 as an unusual association between lymphatic vessels and superficial veins related to cancer development, regardless of surgical treatment. However, Aboul-Enein et al.³⁷ identified such a change in the limb homolateral to surgery, regardless of the presence of lymphedema, associating the finding with the blockage of lymphatic collectors because of the ALND. In addition, this study observed a higher blood flow velocity in brachial vein in the ALNDG and in the brachial artery in the SLNBG before surgery than in the CG.

Celebioglu et al.³⁸ evaluated the lymphatic circulation after ALND and SLNB, concluding that the lymphatic drainage in the operated upper limb had been less affected by the latter than the former, including the related morbidity. These data corroborate with this study, because the results demonstrate that the brachial venous blood flow was more affected in the ALNDG.

The reorganization of the afferent and efferent lymphatic vessels after surgery takes 6–8 weeks.³⁹ In this study, data collection was performed on average in 7 weeks for ALNDG and SLNBG, which corresponds to the period in which afferent and efferent vessels of venous circulation were not entirely reconstituted. This fact can explain the difference in venous flow before and after surgery, which was significant in ALNDG.

Arterial blood flow increases and venous blood flow decreases with the presence of lymphedema in the affected limb after mastectomy.⁴⁰ Valinote et al.⁴¹ reported changes in the lymphatic and venous circulations in women subjected to mastectomy with ALND. Pain et al.⁴² followed up 70 women before breast cancer surgery and 3–12 months after to assess venous changes by using a Doppler device and found a significant reduction in the venous blood flow after 12 months of surgery. Agreeing with these findings, this study shows a decrease in blood flow velocity in brachial vein after ALND. The raw values of SLNBG point to a decreasing trend in the venous blood flow after surgery, a fact that might be significant in a larger sample.

Asymptomatic lymphatic dysfunction can be reported frequently by lymphoscintigraphy in the limb contralateral to the surgery in individuals with lymphedema.⁴³ Alterations in limb contralateral were found in this study with a decreased blood flow velocity in brachial vein after surgery in the ALNDG, and a higher blood flow velocity in brachial vein in the ALNDG and brachial artery in the SLNBG before surgery when compared with the CG.

In a literature review, Celebioglu et al.³⁸ reported vascular alterations resulting from the axillary surgery, including their chronifications, which may trigger lymphedema, force deficit, and axillary web syndrome, among others, thus reinforcing the notion that vascular impairment requires greater attention.

In conclusion, considering the sample population studied, it was found that the group of women undergoing ALND and SLNB had alteration in venous and arterial blood circulation before and after surgery.

Footnotes

Acknowledgment

We thank the Foundation for Research Support of the State of São Paulo (FAPESP) for financial aid.

Author Disclosure Statement

No competing financial interests exist.

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