1. Background
Breast cancer (BC) is the most common cancer and a significant health concern in females, causing cancer-related deaths worldwide (1, 2). According to the American Cancer Society, approximately 287,850 new cases of BC were reported in 2022, with 530 men and 43,250 women expected to die in 2022 (3). In 2018, BC accounted for 10% of all cancer types in Asia, with 845,400 patients (1). It is predicted that the number of new patients in Asia will reach 1.34 million by 2040 (4). In a 2018 study, BC constituted 16% of all reported cancers in Iran, with more than 40% of patients aged between 40 - 50 years (5). Lifestyle changes, smoking, alcohol, obesity, delay in childbearing, and reduced breastfeeding contribute to the increase of BC in low and middle-income countries, accounting for more than 55% of BC deaths (6, 7).
Common medical treatments for BC include a combination of surgeries (such as breast removal and axillary lymph node dissection (ALND), radiation therapy, chemotherapy, and hormone therapy (8) Since there are about 10 - 30 lymph nodes (LNs) below the axillary vein, to which the breast lymph drains (9), in the past, all of them were removed during breast surgery. Later, it was found that according to the surgeon's opinion, the removal of 10 - 12 LNs is sufficient (10). Of course, later, instead of removing all or most of the axillary LNs, the first lymph node that exists after the breast tissue and is called the sentinel lymph node (SLND) was removed and examined. The condition of this LNs indicates the condition of the other LNs, and if it is involved, the axillary LNs must be removed completely (11). Therefore, recently in surgery, the process of local treatment of BC has changed from removing a large number of axillary lymph nodes (ALND) to sentinel lymph node biopsy (SLNB) in people who are clinically negative in the axilla (12). As a result of BC treatment (removal and surgery of LNs, radiation therapy followed by lymphatic system destruction), complications occur (13).
Lymphedema is a significant cause of morbidity in BC patients undergoing axillary surgery (8), resulting from the long-term accumulation of fluid rich in protein due to lymphatic injury during surgery (14). Symptoms include swelling, heaviness, and stiffness in the affected extremity, impacting the overall quality of life (8, 14). Recognizing associated risk factors is essential to decrease the incidence of lymphedema (15).
Sentinel lymph node biopsy is widely accepted for axillary staging in early BC, even in patients positive for axillary lymph nodes (16). Increased use of SLNB has reduced the incidence of lymphedema, but some cases still develop it following SLNB (15). The number of retrieved sentinel lymph nodes during SLNB can influence its accuracy, and a higher count may lead to a higher prevalence of lymphedema in the ipsilateral arm (17, 18). Recent studies suggest that lymphedema might be a morbidity in SLNB-negative patients (19).
1.1. Hypothesis
We hypothesize that patients who undergo the removal of less than 5 sentinel nodes are at a lower risk of developing lymphedema.
2. Objectives
This study aims to explore the relationship between lymphedema and the number of removed negative axillary lymph nodes in SLNB after negative SLNB in females with BC.
3. Methods
3.1. Study Design
This study, conducted from 2016 to 2019, included 1 150 women meeting the study inclusion criteria out of 1 600 BC patients who underwent axillary SLNB at the Cancer Research Center, Shahid Beheshti University of Medical Sciences. The study had a fundamental-applied design, measuring lymphedema after SLNB surgery.
3.2. Sampling
In this cross-sectional research, 950 women with BC who had breast-conserving surgery and underwent sentinel lymph node surgery at least 3 years before the study were selected as study samples. Excluded were 200 patients who underwent simpler subcutaneous mastectomy without radiotherapy.
Inclusion criteria was as follow: (1) Patients must have a history of BC; (2) referral to Cancer Research Center, Shahid Beheshti University of Medical Sciences; (3) the age of the women was between 30 and 60 years; (4) all patients had a negative SLNB result; (5) at least 3 years have passed since treatment; (6) he patient's consent to participate in the research was obtained; (7) all patients had Breast Conserving surgery; (8) none of the patients had previously been treated for postoperative lymphedema, had no history of preoperative lymphedema, orthopedic disorders, neurological problems on the affected side; (9) have secondary edema of the upper limb on the side of the affected breast; (10) have a difference in circumference of > 2 cm compared to that of the contralateral extremity for either the forearm or the upper arm.
Exclusion criteria was as follow: (1) Patients unwilling to participate in the research for any reason; (2) had a history of axillary lymph node removal; (3) patients who exhibited a positive result in their sentinel lymph node biopsy (SLNB); (4) patients who did not undergo radiotherapy.
3.3. Methods
All eligible patients after sentinel lymph node biopsy were contacted to obtain their medical history and pathology documents. A questionnaire related to background information and clinical evaluation, including body mass volume and lymphedema measurement, was completed. The evaluation included a clinical examination by a cancer surgeon and lymphotherapist at the center's lymphedema clinic. A demographic information questionnaire with 20 questions was completed for each patient.
Lymphedema was evaluated by objective assessment of the upper limbs and subjective measurement of symptoms. Using non-stretch tape, an experienced researcher measured the difference in circumference between two affected organs and healthy organs in four parts: Palm, wrist, 10 cm below, and 10 cm above the first cranial appendage of the elbow. A lymphedema patient had a difference in circumference of more than 2 cm compared to that of the contralateral extremity for either the forearm or the upper arm.
3.4. Statistical Analysis
Quantitative variables were described using mean and standard deviation, while qualitative variables were reported as numbers (percentages). t-test and chi-square tests were used to analyze the correlation between different variables and the number of lymph nodes after the removal of sentinel lymph node-negatives in women with breast cancer. Data were analyzed using Stata software (version 14), and P < 0.05 was considered statistically significant.
4. Results
In this study, 950 women with breast cancer (BC) having axillary sentinel LN-negatives and undergoing radiotherapy were recruited. 4% of patients (38 individuals) experienced lymphedema. The patients' average age was 56.74 ± 7.68 years (age range: 39 to 71 years), and the average age in patients with lymphedema was significantly lower compared to patients without lymphedema (53.34 years vs. 56.88 years) (P = 0.005). The mean body mass index (BMI) was 27.43 ± 4.14 kg/m², and its average did not show a significant difference between the two groups with lymphedema and without edema (P = 0.577). Additionally, the average number of sentinel LN-negatives removed was 1.64 ± 0.97 (ranging from 1 to 5 nodes) in patients. The average number of LN-negatives in patients with edema was significantly higher than in patients without edema (4.89 ± 0.31 vs. 1.51 ± 0.73) (P < 0.001) (Table 1).
Table 1.Description of the Variables of Age, BMI, and the Number of Lymph Node-Negatives According to the Occurrence of Lymphedema in Patients with Breast Cancer a
| Different Variables | Total: 950 | Yes: 38 | No: 912 | P-Value b |
|---|---|---|---|---|
| Age (y) | 56.74 ± 7.68 | 53.34 ± 7.85 | 56.88 ± 7.64 | 0.005 |
| BMI (Kg/m2) | 27.43 ± 4.11 | 27.07 ± 3.69 | 27.45 ± 4.13 | 0.577 |
| Number of removed sentinel lymph node-negatives | 1.64 ± 0.97 | 4.89 ± 0.31 | 1.51 ± 0.73 | > 0.001 |
a Values are expressed as mean ± SD.
b Using the chi-square test.
Based on BMI levels, 28.11% of patients were in the normal group, 43.79% in the overweight group, and 28.11% in the obese group. Regarding marital status, most women, both in general and among patients with and without lymphedema, were married. In terms of education level, the majority had primary and middle school education. Among all patients, 52.11% (495 individuals) had a history of underlying diseases. In 52.11% of all patients, the affected limb was on the right side. No statistically significant relationship was found between the mentioned variables and the occurrence of lymphedema (P > 0.05) (Table 2).
Table 2.Frequency of Demographic and Disease-related Variables According to the Occurrence of Lymphedema in Breast Cancer Patients a
| Variables | Total: 950 | Yes: 38 | No: 912 | P-Value b |
|---|---|---|---|---|
| BMI | 0.484 | |||
| Normal | 264 (28.11) | 10 (26.32) | 257 (28.18) | |
| Overweight | 416 (43.79) | 20 (52.63) | 396 (43.42) | |
| Obesity | 267 (28.11) | 8 (21.05) | 259 (28.40) | |
| Marital status | 0.166 | |||
| Single | 58 (5.11) | 5 (13.16) | 53 (5.81) | |
| Madrid | 851 (89.58) | 31 (81.58) | 820 (89.91) | |
| Divorce | 41 (4.32) | 2 (5.26) | 39 (4.28) | |
| Level of education | 0.178 | |||
| Elementary school | 382 (40.21) | 15 (39.47) | 367 (40.24) | |
| High school | 296 (31.16) | 7 (18.42) | 289 (31.69) | |
| Diploma and sub-diploma | 217 (22.84) | 12 (31.58) | 205 (22.48) | |
| University | 55 (5.79) | 4 (10.53) | 51 (5.59) | |
| Underlying disease | 0.947 | |||
| Yes | 495 (52.11) | 20 (52.63) | 475 (52) | |
| No | 455 (47.89) | 18 (47.37) | 437 (47.92) | |
| Affected organ | 0.947 | |||
| Right | 495 (52.11) | 20 (52.63) | 475 (52) | |
| Left | 455 (47.8) | 18 (47.37) | 437 (47.92) |
a Values are expressed as No. (%).
b Using the chi-square test.
There was a significant relationship between the number of removed LN-negatives and the occurrence of lymphedema, so that with the increase in the number of LNsto 4 and 5 nodes, the occurrence of lymphedema in patients was 10.53% and 89.47%, respectively, but in patients with 1-3 LNs, the percentage of lymphedema was zero (Table 3).
Table 3.The Frequency of the Number of Lymph nodes According to the Occurrence of Lymphedema in Patients with Breast Cancer a
| Number of Removed Sentinel Lymph Node-Negatives | Total: 950 | Yes: 38 | No: 912 | P-Value b |
|---|---|---|---|---|
| 1 | 572 (60.21) | 0 (0) | 62.72 (572) | > 0.001 |
| 2 | 211 (22.21) | 0 (0) | 23.14 (211) | |
| 3 | 129 (13.58) | 0 (0) | 14.14 (129) | |
| 4 | 4 (0.42) | 4 (10.53) | 0 (0) | |
| 5 | 34 (3.58) | 34 (89.47) | 0 (0) |
a Values are expressed as No. (%).
b Using the chi-square test.
5. Discussion
The sentinel lymph node biopsy (SLNB), introduced over 15 years ago in clinically node-negative BC patients, serves to assess their LN status for diagnostic purposes (20). In cases of a negative SLN, an axillary lymph node dissection (ALND) is omitted. The SLN is negative in about 74% of patients in the general BC population (21). Lymphedema is a non-negligible complication in cases of SLNB-negative BC (22), observed in one of five cases with BC, following radiation therapy, breast surgery, and chemotherapy (23). SLNB stages the clinically negative axilla (19), and the prevalence of lymphedema (LE) following SLNB is nearly 5% (24). Patients receiving axillary excision of more than five LNs are more prone to develop LE (25, 26). Risk factors for LE include LN dissection, high BMI, mastectomy, the number of affected LNs, lack of regular physical activity, and receiving radiation therapy and chemotherapy. However, in our study, no significant difference in average BMI was observed between the two groups (with and without edema) (27-29).
We investigated the association between lymphedema and the number of removed axillary LN-negatives in SLNB in BC patients. The patients' average age was 56.74 ± 7.68, and the average BMI was 27.43 ± 4.14 kg/m2, with an average follow-up period after surgery of 3 years. Based on BMI, 43.42% of the group were overweight. The number of retrieved LN-negatives can be considered a risk factor for LE development. Lymphedema occurs after surgery in some patients and affects their quality of life (30). We found a significant relationship between the number of isolated LN-negatives and LE (4.89 ± 0.31 versus 1.51 ± 0.73) (P < 0.001). The relationship between the number of removed LN-negatives and the occurrence of lymphedema was significant, with 10.53% and 89.47% occurrence rates in patients with 4 and 5 nodes, respectively, and zero incidence in patients with 1 - 3 LNs. In Gebruers's study, the general incidence of lymphedema after SLNB in nodes-negative cases was reported broadly (0% to 63.4%) (22).
We found an association between the number of removed LN-negatives had a significant relationship with the occurrence of lymphedema, so that with the increase in the number of LNs to 4 and 5 nodes, the occurrence of lymphedema in patients was 10.53% and 89.47%, respectively, but in patients with 1 - 3 LNs, the percentage of lymphedema was zero (Table 3).
Isik et al. reported in 2022, in a retrospective study of the BC database from 2013 to 2017, that patients with removal of more than 5 LNs were more likely to develop lymphedema (25). A 2022 study by Yaghoobi Notash et al., aiming to determine factors influencing lymphedema which was done on 970 patients with BC, the percentage of influencing variables was reported as follows: The number of LNs/the number of LNs isolated ratio (68%), the feeling of heaviness (67%), number of LNs isolated (64%), receiving radiotherapy (63%), surgery type (62%), number of involved LNs (61%), BMI (61%) (31). So both of these studies showed a significant association between the number of isolated LN-negatives and Lymphedema in patients same our study.
Sentinel lymph node biopsy-negative patients may exhibit mild lymphedema, but if untreated, it can become more severe. However, in our study, severe lymphedema was diagnosed in 4% of patients, which falls within the recorded range of 0.2% to 9% in SLNB patients with lymphedema in some studies (15, 32-35). Therapists and clinicians should consider lymphedema as a complication when evaluating patients who have had SLNB. Although our study evaluated lymphedema over a period of at least 3 years, some studies suggest a critical follow-up period of 6 - 12 months following surgery to assess the presence of lymphedema in such cases (36, 37).
5.1. Conclusions
Lymphedema is a morbid and chronic complication resulting from BC treatment using axillary surgery and/or radiation treatment which causes psychological and functional problems affecting patients’ quality of life. For this reason, prognostic factors help a lot in treating and reducing complications. In our study, a positive association was reported between the number of removed LN-negative in axillary SNB and the degree of lymphedema in patients, although more studies are needed in this field to obtain more accurate results.
