Abstract
In this study, our aim was to evaluate the role of lymphovascular invasion (LVI) in the prognosis of patients with early stage breast cancer. The medical records of more than 7000 patients who suffered from invasive breast cancer and had undergone surgical treatment since December 1994 till December 2019, retrospectively. Patient’s history, physical examination and the clinicopathological features, histopathology characteristics, immunohistochemical findings, adjuvant systemic therapy, recurrence rate, metastasis-free survival (MFS), disease-free survival (DFS), and overall survival (OS) were reviewed. A total of 5425 eligible patients were categorized into two groups based on the presence of LVI; 3031 (55.9%) patients had no LVI (group 1) and LVI was present in 2394 (44.1%) patients (group 2), then divided into LN-positive and -negative groups. Presence of LVI was significantly associated with patient age ≤ 40 years (p = 0.048), high histological grade (grades II and III, p < 0.001), tumor size between 2–5 cm and > 5 cm (p < 0.001), number of involved LN ≥ 4 (p < 0.001), and negative ER (p = 0.042) tumors. Five-year OS, MFS, and DFS were 93%, 88.9%, and 76.1% and 85.2%, 84.7%, and 73.6 in groups 1 and 2, respectively (P < 0.001). On multivariate analysis, LVI was an independent prognostic factor for DFS in all patients. Furthermore, histological grade II, histological grade III, and a higher number of involved LNs (≥ 4) were independent predictors in all patients. Thus, the presence of LVI can be considered as an independent prognostic factor for patients with operable breast cancer, irrespective of the LN status.
Keywords: Breast cancer, Lymphovascular invasion, Prognosis, Survival, Lymph node
Introduction
Among female malignancies, breast cancer is at the top of the list and is a major cause of mortality [1]. At present, axillary lymph node (LN) involvement, tumor size, nuclear grade, hormone receptor status, and patient age are among the most recognized prognostic factors in a patient with breast cancer who is a candidate for surgery [2]. Since LN involvement is the presenting sign of the potential for distant metastasis, it is considered the most determining prognostic factor of all [3, 4].
Distant metastases are the leading cause of mortality of breast cancer. Metastasis occurs via lymphatic and/or blood spreading of the tumor cells (lymphovascular invasion or LVI) and is defined as tumor emboli covering the endothelial-lined spaces in breast tissue surrounding the invasive carcinoma [4]. In the presence of LVI, there is an increased risk of tumor cell spreading and hence developing lymph node positivity or distant metastasis [5]. It is shown that the presence of LVI is correlated with tumor size, patients’ age, histologic type, and grade of the tumor, and is an independent prognostic factor in the survival of lymph node-negative patients with breast cancer [6]. In one study, it was shown that LVI was associated with decreased survival in node-negative patients and also conferred worse prognosis in patients with 1–3 positive nodes; however, it had no additional impact in patients with 4–9 positive nodes [3]. In a cohort study by Ejlertsen et al., it was found that LVI was not an independent risk factor for patients with breast cancer and LVI was not a poor prognostic factor in low-risk patients [7].
Another study concluded that LVI is the single most important determining factor in the survival of patients with breast cancer, especially the node-negative ones and should be included in staging systems [8]. A meta-analysis by Zhang et al. showed that LVI is a weaker prognostic factor than lymphatic vessel density in patients with breast cancer but it was also accompanied by worse survival [9]. There is still debate on the precise impact of LVI in node-positive and node-negative patients. So, in this study, we aim to evaluate the effect of LVI in patients with node-positive and node-negative breast cancer in south of Iran.
Patients and Methods
Study Settings
This survey was led in Shiraz Breast Clinic, Shiraz, Iran, which is the main referral center for breast cancers in the South of Iran. The registry is affiliated to Shiraz University of Medical Sciences and contains data on in excess of seven thousand breast cancer patients. Shiraz Breast Cancer Registry (SBCR) includes information on financial status, clinical history and examination, histopathological characteristics, imaging, follow-up, and prognosis data of all patients with breast cancer.
Study Protocol
In this retrospective study, the medical records of more than 7000 patients who suffered from invasive breast cancer and had undergone surgical treatment at the department of surgery, Shahid Faghihi Hospital, Shiraz, Iran, were assessed at Breast Diseases Research Center (Shiraz, Iran), since December 1994 till December 2019. A complete history and physical examination, bilateral breast mammography, chest X-ray radiology, and routine blood and biochemical tests were required for all patients prior to surgery. Exclusion criteria of the study were as follows: male gender, previous, or concurrent contralateral breast cancer, neoadjuvant chemotherapy, having prior malignancy, and incomplete follow-up information.
Eight hundred eighty patients were excluded due to being treated with neoadjuvant chemotherapy and 260 patients had bilateral disease. Patients had been surgically treated with either breast conservation methods or mastectomy with SLNB, AND, or a combination of them, followed by postoperative radiation therapy in some cases. Whether the patients needed adjuvant systemic therapy (chemotherapy and hormonal therapy) was determined based on the axillary lymph node status, hormone receptor status, and menopausal status.
Clinicopathologic Examination
The clinicopathological features, including the side of breast involvement; size of the tumor; operation types (lumpectomy vs. mastectomy); SLNB and AND for axillary management; histopathology characteristics including histological grade; subtype and LVI status; immunohistochemical findings such as estrogen receptor (ER), progesterone receptor (PR), and HER 2 status; adjuvant systemic therapy (hormone therapy; radiotherapy; and chemotherapy); and recurrence rate, disease-free (DFS), and overall survival (OS) were reviewed, retrospectively.
Patients were subgrouped according to their age (< 40 years and ≥ 40 years) at the time of tumor diagnosis. Tumor size was measured as the largest diameter on the pathologic specimen which was stained by hematoxylin and eosin (H&E) and tumor grading was based on the highest nuclear grade found on the specimen and was defined as I to III.
Hormone receptor status was evaluated by immunohistochemistry (IHC) and was considered ER or PR positive if it had ≥ 1% expression.
HER2 status was also assessed by IHC and HER2/chromosome 17 fluorescence in situ hybridization when necessary.
LVI was considered as the presence of carcinoma cells emboli in an endothelial-lined space (whether lymphatic channels or blood vessels) on the H&E slide. LVI must be assessed at a distance of at least one high-power microscopic field away from the tumors, in the normal breast tissue surrounding the carcinoma [5, 6, 10].
Statistical Analysis
The chi-square test was used for the comparison of qualitative data. One-way ANOVA and Kruskal–Wallis tests were used for normal distribution and without a normal distribution quantitative data, respectively. The Kaplan–Meier analysis was utilized for OS and DFS data. DFS was defined as the length of time from surgery to recurrence of breast cancer (local, regional, or distant). OS was defined as the length of time from surgery to death from any cause. The significance of differences in survival rates was evaluated using the log-rank test. Kaplan–Meier was also used to estimate the survival experience of different groups of prognostic factors. Multivariate analyses were performed using the Cox regression model. All analyses were performed using SPSS software ® for windows®, version 21.0, and a P-value less or equal to 0.05 was considered statistically significant.
Results
In this study, 5425 patients were eligible for evaluation in this analysis. Patients were categorized into two groups based on the presence of LVI; 3031(55.9%) patients had no LVI (group 1) and LVI was present in 2394 (44.1%) patients (group 2).
Also, according to the existence of LN involvement, each group was further divided into LN-positive and LN-negative groups.
Patients’ Clinicopathological Features
Comparison of baseline and clinical characteristics between these two groups according to the pathological subtype showed that the groups were significantly different regarding tumor size, tumor grade, molecular subtype, and LN involvement. Table 1 presents an overview of clinicopathological characteristics between the two groups.
Table 1.
Clinicopathological data of patients
| Characteristics | Lymphovascular invasion (LVI) | Total | P-value | ||
|---|---|---|---|---|---|
| No N = 3031 (55.9) |
Yes N = 2394 (44.1) |
||||
| Age (yr) | 0.048 | ||||
| < 40 | 799 (26.4) | 661 (27.6) | 1460 (26.9) | ||
| > 40 | 2232 (73.6) | 1733 (72.4) | 3965 (73.1) | ||
| Tumor size | < 2 | 1177 (38.8) | 627 (26.2) | 1804 (33.3) | < 0.001 |
| 2–5 | 1745 (57.6) | 1636 (68.3) | 3381 (62.3) | ||
| > 5 | 109 (3.6) | 131 (5.5) | 240 (4.4) | ||
| Grade | I | 648 (26.5) | 339 (15.9) | 987 (21.6) | < 0.001 |
| II | 1271 (52.0) | 1346 (63.2) | 2617 (57.2) | ||
| III | 444 (21.5) | 525 (20.9) | 969 (21.2) | ||
| No. of positive LN | < 0.001 | ||||
| 1 | 248 (24.3) | 164 (16.2) | 412 (20.3) | ||
| 2 | 170 (16.6) | 131 (12.9) | 301 (14.8) | ||
| 3 | 112 (10.9) | 94 (9.2) | 206 (10.1) | ||
| > 4 | 490 (48.0) | 622 (61.5) | 1112 (54.7) | ||
| ER | Negative | 765 (26.3) | 627 (27.4) | 1393 (26.8) | 0.042 |
| Positive | 2149 (73.7) | 1658 (72.6) | 3807 (73.2) | ||
| PR | Negative | 936 (32.3) | 773 (33.9) | 1709 (33.0) | 0.114 |
| Positive | 1960 (67.7) | 1504 (66.1) | 3464 (67.0) | ||
| HER-2 | Negative | 1752 (74.0) | 1255 (68.2) | 3007 (71.5) | < 0.059 |
| Positive | 616 (26.0) | 584 (31.8) | 1200 (28.5) | ||
The median age of patients included in the study was 48 years (ranged 18 to 97 years) and the median follow-up period was 57.86 months (min: 0, max: 290).
LVI was present in 44.1% of patients and was significantly associated with patient age ≤ 40 years (p = 0.048), high histological grade (grades II and III, p < 0.001), tumor size between 2–5 cm and > 5 cm (p < 0.001), number of involved LN ≥ 4 (p < 0.001), and negative ER (p = 0.042) tumors. But, it was not related to PR status and HER2 receptor status (Table 1). Surgical treatment was not significantly associated with the presence of LVI.
Survival Outcomes of Two Groups
Table 2 shows the recurrences and survival outcomes of patients. During the follow-up period, the number of distant metastases was 348 (11.4%) and 439 (18.3%) in groups 1 and 2, respectively. The number of locoregional recurrences was 72 (2.3%) in group 1 and 88 (3.6%) in group 2. One thousand twenty-eight (12.85%) patients died due to breast cancer during the study. Five-year OS, MFS, and DFS were 93%, 88.9%, and 76.1% and 85.2%, 84.7%, and 73.6 in groups 1 and 2, respectively (P < 0.001) (Fig. 1).
Table 2.
Univariate analysis of LVI adjusted whit nodal involvement
| Lymphovascular invasion | |||||||
|---|---|---|---|---|---|---|---|
| NO (N = 3031) | P-value | Yes (N = 2394) | P-value | ||||
| Nodal involvement | Nodal involvement | ||||||
| No (N = 891) | Yes (N = 646) | No (N = 542) | Yes (N = 1347) | ||||
| Axillary management | SLNB | 364 (50.0) | 246 (48.3) | 0.539 | 77 (21.2) | 200 (20.6) | 0.837 |
| AND | 291 (40.0) | 202 (39.7) | 239 (65.7) | 624 (64.3) | |||
| SLNB + AND | 73 (10.0) | 61 (12.0) | 48 (13.2) | 147 (15.1) | |||
| Tumor size (cm) | < 2 | 355 (39.8) | 302 (26.4) | 0.091 | 120 (22.1) | 353 (26.2) | 0.779 |
| 2–5 | 493 (55.3) | 794 (69.3) | 390 (70.0) | 912 (67.7) | |||
| > 5 | 43 (4.8) | 50 (4.4) | 32 (5.9) | 82 (6.1) | |||
| Grade | I | 194 (26.5) | 123 (23.3) | 0.363 | 77 (16.1) | 187 (15.5) | 0.563 |
| II | 392 (53.6) | 289 (54.7) | 309 (64.5) | 758 (62.7) | |||
| III | 145 (19.8) | 116 (22.0) | 93 (19.4) | 263 (21.8) | |||
| No. of positive LN | 1 | 68 (19.6) | 53 (21.7) | 0.248 | 38 (19.0) | 91 (18.7) | 0.048 |
| 2 | 52 (15.0) | 37 (15.1) | 29 (14.7) | 73 (15.0) | |||
| 3 | 33 (9.5) | 22 (9.0) | 19 (9.5) | 54 (11.1) | |||
| > 4 | 193 (55.7) | 132 (54.1) | 113 (56.7) | 268 (55.1) | |||
| ER | Negative | 216 (25.2) | 183 (29.2) | < 0.026 | 138 (26.5) | 371 (28.9) | 0.062 |
| Positive | 640 (74.8) | 443 (70.8) | 383 (73.5) | 912 (71.1) | |||
| PR | Negative | 266 (31.3) | 222 (35.7) | 0.043 | 178 (34.5) | 444 (34.6) | 0.514 |
| Positive | 584 (78.7) | 400 (64.3) | 338 (65.5) | 841 (65.4) | |||
| HER-2 | Negative | 472 (69.7) | 370 (71.6) | 0.055 | 284 (68.1) | 681 (66.6) | 0.035 |
| Positive | 205 (30.3) | 147 (28.4) | 133 (31.9) | 342 (33.4) | |||
| Chemotherapy | No | 584 (84.7) | 422 (73.5) | 0.063 | 359 (73.0) | 720 (62.1) | 0.002 |
| Yes | 198 (25.3) | 152 (26.5) | 133 (27.9) | 440 (37.9) | |||
| Radiotherapy | No | 224 (29.7) | 35 (6.5) | < 0.001 | 111 (23.3) | 63 (5.8) | < 0.001 |
| Yes | 531 (73.3) | 506 (93.5) | 365 (76.7) | 1028 (94.2) | |||
| Hormonal therapy | No | 161 (20.6) | 140 (25.7) | 0.005 | 103 (23.6) | 229 (20.8) | 0.129 |
| Yes | 619 (79.4) | 405 (74.3) | 334 (76.4) | 873 (79.2) | |||
| Recurrence | No | 726 (83.2) | 528 (82.8) | 0.109 | 385 (73.1) | 983 (74.9) | 0.140 |
| Yes | 147 (16.8) | 110 (17.2) | 142 (26.9) | 330 (25.1) | |||
| Survival | Alive | 797 (91.1) | 568 (89.6) | < 0.001 | 420 (79.8) | 1092 (83.6) | < 0.001 |
| Death | 78 (8.9) | 66 (10.4) | 106 (20.2) | 215 (16.4) | |||
| Median follow-up (months) | 59.29 | 57.6 | 0.241 | 67.2 | 60.3 | < 0.002 | |
Fig. 1.
Overall survival (OS) and disease-free survival (DFS) of whole patients. A OS curves are shown according to the presence or absence of lymphovascular invasion (LVI). B DFS curves according to presence or absence of LVI are shown
In group 1, 5-year OS was 84% for patients with nodal involvement and 92% for patients without nodal involvement (P < 0.001) and DFS was 76% vs 83% (P = 0.022) (Fig. 2).
Fig. 2.
A Overall survival (OS) of patients in whom with no LVI (group1) according to the lymph node (LN) involvement. B Disease-free survival (DFS) of patients in group 1 according to the LN involvement. C OS of patients in whom with LVI (group 2) according to the LN involvement, D DFS of patients in group 2 according to the LN involvement
In group 2, 5-year OS was 82% for patients with nodal involvement and 90% for patients without nodal involvement (P < 0.001) and DFS was 82% vs 89% (P = 0.016) (Fig. 2).
Univariate and Multivariate Analysis
In univariate analysis, factors that were associated with better 5-year DFS were as follows: tumor size < 2 cm, hormone receptor status (positive ER, PR), HER2 receptor status (negative), absence of LVI, and low histological grade (grade I) (P < 0.05). The number of lymph node involvement (> 4) was associated with poor DFS. Table 2 presents the univariate analysis according to the lymph node involvement.
LVI was an independent prognostic factor for DFS in all patients (relative risk (RR), 2.23; 95% confidence interval (CI), 1.624–3.826; p = 0.01). Furthermore, histological grade II (RR 1.66; 95% CI, 0.674–3.948; p = 0.033), histological grade III (RR, 2.77; 95% CI, 1.154–8.781; p = 0.012), and a higher number of involved lymph nodes (≥ 4; RR, 1.75; 95% CI, 1.390–2.195; p < 0.001) were independent predictors in all patients. However, age, tumor size, hormone receptor status, and HER2 status were not significant independent factors. Table 3 presents the disease-free survival (DFS) multivariate analysis in the whole group of patients.
Table 3.
Disease-free survival (DFS) multivariate analysis in the whole group of patients
| Patient characteristic | RR | 95% CI | P-value |
|---|---|---|---|
| LVI | 2.237 | 1.624–3.826 | 0.010 |
| Grade II | 1.66 | 0.674–3.948 | 0.033 |
| Grade III | 2.777 | 1.154–8.781 | 0.012 |
| > 4 involved lymph node | 1.752 | 1.390–2.195 | < 0.001 |
In the hormone receptor-positive group, positive LVI (p = 0.016), number of involved lymph nodes (p = 0.019), and histological grade III (p = 0.033) were also independent factors for a poor prognosis.
Discussion
Different prognostic factors of invasive breast cancer have been investigated in various studies. Poor prognosis was seen in association with involvement of axillary lymph node, age, high histological grade, large tumor size, and negative hormone receptor status, which affect the DFS and OS [5]. Also, LVI plays a significant role as an independent poor prognostic factor in patients suffering from invasive breast cancer, regardless of lymph node status [11, 12]. However, there is controversy about its role in the prognosis of invasive breast cancer regarding the lymph node status. For instance, Ejlertsen et al. concluded that LVI should not be considered as an independent prognostic factor and is not strong enough to place a patient in a high-risk group [7], while Woo et al. study showed that LVI was a strong poor prognostic factor in patients with 0 to 3 LN involvement and had no additive effect in patients with more LN involvement [3].
According to this controversy and inconsistent results about the proper prognostic role of LVI in patients with invasive breast cancer, in our large cohort study, we evaluated the prognostic significance of LVI in LN-positive and LN-negative patients with operable invasive breast cancer.
In this retrospective study, the prevalence of LVI was 44.1% which is similar to previous studies (range 21 to 51%) [8, 12–14]. LVI was considered as an independent poor prognostic factor for DFS (RR: 2.23, P = 0.01) in all patients, regardless of the presence or absence of LN involvement in multivariate analysis. In contrast, Colleoni et al. demonstrated that LVI is a poor prognostic factor in node-negative patients; however, patients with more than 3 LN involvement were not included in their study [14].
Besides LVI, our study showed that histological grades II, III, and a high number of involved lymph nodes (≥ 4) were other important independent prognostic factors.
It seems that LVI is independent from other factors. Our study demonstrated that LVI is a prognostic factor in lymph node-positive and -negative patients. However, the patient’s age, tumor size, hormone receptor status, and HER-2 status were not independent prognostic factors.
In our study, the presence of LVI was associated with a statistically significant lower 5-year OS, MFS, and DFS and its prognostic value was independent of other prognostic factors. Also, this study showed that LVI was correlated with a higher rate of locoregional recurrences and distant metastasis. Some previous studies have demonstrated that LVI has an independent causative role in patients with increased local recurrence and distal metastasis [15–19]. But, Rakha et al. found no association between LVI and increased local recurrence [8]. Patients with positive hormone receptors were analyzed separately and it was shown that these patients were negatively influenced by the presence of LVI, number of positive LNs, and histological grade as independent factors which emphasize the importance of LVI detection in these patients and the fact that they may need to receive adjuvant therapy besides their conventional treatment protocol.
LVI has been shown to be correlated with age of patients, tumor size, grade, and histologic type in many studies [6, 12, 22] which was confirmed in our study, too. Besides we found that LVI is also associated with a number of involved lymph nodes ≥ 4 (p < 0.001) and negative ER (p = 0.042) but not with positive PR or HER2 status.
Like Colleoni et al., Goldhirsch et al. study showed that LVI must be extensive to be strong enough to put the patient in the high-risk category [14, 20]; however, in concordance with Rakha et al., our study showed the importance of the presence of LVI irrespective of its extent [8].
Proper LVI detection is highly dependent on precise tissue handling, fixation, and preparation which was done in our study in a standard and optimized fashion and this important issue can greatly influence the rate of LVI detection, histopathologic grade, HER2, and HR status [21].
There were several limitations. This study had a retrospective nature. The presence of LVI was investigated by H&E staining and selective endothelial markers such as CD-34 and D2-40 were not used which could help better identify more cases with LVI.
In conclusion, the presence of LVI can be considered as an independent prognostic factor for patients with operable breast cancer, irrespective of the lymph node status.
Data Availability
All data and materials as well as software application or custom code support the published claims and comply with field standards.
Code Availability
SPSS software ® for windows®, version 21.0
Declarations
Ethics Approval
This research study was conducted retrospectively from data obtained for clinical purposes. We consulted extensively with the Ethics Committee of Shiraz University of Medical Sciences, Who determined that our study did not need ethical approval.
Consent to Participate
Informed consent was obtained from all individual participants included in the study.
Consent for Publication
Informed consent was obtained from all individual participants included in the study.
Conflicts of Interest
The authors declare that they have no conflict of interest.
Footnotes
Publisher's Note
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
All data and materials as well as software application or custom code support the published claims and comply with field standards.
SPSS software ® for windows®, version 21.0