Acta chir belg, 2007, 107, 284-287
Lymphovascular Invasion, as a Prognostic Marker in Patients with Invasive Breast Cancer G. Gurleyik*, E. Gurleyik**, F. Aker***, A. Aktekin*, S. Emir*, O. Gungor*, A. Saglam* Departments of Surgery* and Pathology***, Haydarpasa Numune Education and Research Hospital, Istanbul ; Department of Surgery**, AIBU Duzce Medical Faculty, Duzce, Turkey.
Key words. Breast cancer ; axilla ; lymphovascular invasion ; metastasis. Abstract. Purpose : The markers of prognosis are used to predict the clinical course of disease and the outcome for patients with invasive breast cancer. Our aim is to investigate the relationship of peritumoural lymphovascular invasion (LVI) with well-known prognostic markers. Patients and Methods : Eighty-one surgically treated patients with invasive breast cancer were evaluated in this study during a mean follow-up period of 46 months (12-72). The patient’s age (menopausal status), tumour size, nuclear grade, axillary lymph node involvement, and hormone receptor status were determined as markers of the prognosis. The relationship of LVI with these markers was established. Results : Except for menopausal status (p = 0.25) a close relationship was found between the presence of LVI and studied prognostic factors. LVI was positive in 29% of T1, 54% of T2 (p = 0.028) and 100% of T3 tumours (p = 0.002). The rate of LVI (+) has increased gradually as 0%, 38% and 77% (p = 0.001) with grades 1, 2 and 3 respectively. Positive LVI has been determined in 85% (p < 0.0001) and 73% (p = 0.0004) of oestrogen and progesterone receptor negative tumours respectively. LVI was present in 14% and 73% (p < 0.0001) of patients with negative and positive axilla respectively. Metastatic cancer caused mortality in seven patients of whom 86% had more than four involved axillary nodes, and 100% LVI (+). Conclusion : The high rate of positive LVI shows a close relationship with known markers of poor prognosis. The presence of LVI can predict a worse outcome for patients with invasive breast cancer. LVI may be used as an indicator of aggressive behaviour, metastatic ability (nodal and systemic) of the primary malignancy.
Introduction Prognostic factors can be used to predict the natural history of breast cancer. The decision to apply adjuvant aggressive systemic therapy might be warranted in patients whose prognosis is poorly predicted by using prognostic factors. The presence or absence of metastatic involvement in axillary lymph nodes, tumour size, nuclear grade, hormone receptor status, and patient’s age are well known prognostic factors for patients with invasive breast cancer. Lymph node involvement with the tumour cells is accepted as the most powerful prognostic factor (1, 2). Lymph node involvement reveals that the malignancy has gained the ability of systemic spread and the risk of distant metastasis increases. The presence of tumour emboli within peritumoural endothelial lined spaces was defined as lymphovascular invasion (LVI). The identification of LVI may permit the determination of patients at increased risk for axillary involvement and distant metastases (2, 3). The aim of this study was to investigate the relationship of LVI with well-known prognostic markers and its
predictive role on axillary lymph node involvement and outcome (prognosis) of breast cancer cases. Materials and Methods We evaluated 81 patients with invasive breast cancer in this study during a mean follow-up period of 46 months (12-72). They have been surgically treated by modified radical mastectomy or by wide local excision and sentinel node biopsy followed by axillary dissection. The tumour size was measured macroscopically. Nuclear grade was determined by a modification of the simplified Black technique. Axillary status was evaluated by sentinel lymph node biopsy and by level 1 and 2 axillary dissection. Lymph nodes were identified and stained with haemotoxilen eosin and examined for tumour metastasis. Hormone receptor status was determined by immunohistochemistry. Tumour and peritumoral breast tissue was examined for lymphovascular invasion. The presence of tumour emboli within peritumoural endothelial lined spaces, stained with H and E is defined as positive LVI in accordance with the
LVI, Prognostic Marker for Breast Cancer
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Table I
Table II
The relationship of LVI with prognostic markers of breast cancer
The rate of positive LVI according to markers of poorer prognosis
Pre Menopausal status Post Positive Oestrogen receptor Negative Positive Progesterone receptor Negative Tumour size 0-2 cm 2-5 cm > 5 cm Nuclear grade 1 2 3 Axillary lymph node Negative Positive Positive 1-3 Positive 4-9 Positive > 10
No of patients (n = 81)
LVI (+)
Prognostic Markers
30 (37)*
17 (57)
51 (63) 55 (68)
21 (41) 16 (29)
26 (32) 51 (63)
22 (85) 16 (31)
30 (27) 34 (42) 41 (51) 6 (7) 7 (9) 48 (51) 26 (32)
22 (73) 10 (29) 22 (54) 6 (100) 0 18 (38) 20 (77)
p < 0.001
36 (44) 45 (56) 23 15 7
5 (14) 33 (73) 13 (57) 13 (87) 7 (100)
p < 0.0001 p < 0.0001 p < 0.0001 p < 0.0001
p = 0.2491
p < 0.0001
p = 0.0004 p = 0.028 p = 0.002
* Numbers in parentheses are percentages.
guidelines outlined by PAGE and ANDERSON (4). Studied markers of prognosis were classified according to the presence of LVI in order to establish the relationship of LVI with other markers. Statistical analysis Variables were analyzed using Fisher’s exact test. Univariate analyses of variance were performed by Post-hoc test. A p value of less than 0.05 was considered as significant. Results The mean age of patients at the time of surgery was 55.5 years. Thirty patients (37%) were premenopausal. Oestrogen and progesterone receptors were positive in 55 (68%) and 51 (63%) patients respectively. The difference of LVI (+) was significant according to hormone receptors status. The rate of LVI (+) has increased proportionally and gradually with tumour size and the nuclear grade of primary tumour. Forty-five patients (56%) had axillary involvement. LVI was present in 33 patients (73%) with lymph node metastases (p < 0.0001). Only five patients (14%) had LVI positive tumours in the node negative group (Table I). LVI was positive in all patients with a tumour larger than 5 cm and who had more than ten metastatic lymph nodes. The
Grade 2 T2 Premenopausal PR* negative Axilla positive Grade 3 OR* negative Positive 4-9 nodes T3 Positive > 10 nodes Fatal metastatic disease
Rate of positive LVI (%) 38 54 57 73 73 77 85 87 100 100 100
* OR : Oestrogen receptor, PR : Progesterone receptor.
rate of positive LVI has gradually increased according to more serious indicators of poorer prognosis (Table II). Seven patients, who died from metastatic breast cancer during the follow-up period, had lymph node involvement and LVI (+) tumours. Five patients (71%) were premenopausal, and five (71%) had grade 3 tumour. Six patients (86%) had more than four involved nodes, and six tumours (86%) were hormone receptor negative. All seven patients (100%) had LVI (Table III). Discussion Previous well-designed studies have analyzed the prognostic factors in patients with invasive breast cancer for determining the subgroup of patients who have biologically aggressive tumours. Axillary lymph node involvement, younger age, high nuclear grade, large tumour size and the absence of hormonal receptors were significantly correlated with poor disease-free and overall survival (1). LVI has also been determined to be a significant negative predictor of prognosis in previous studies (2, 3, 5). We tried to assess the relationship of the presence or absence of LVI in tumoral or peritumoral tissue with known prognostic factors of breast cancer in our patients. The prognosis of invasive breast cancer is known to be poorer in premenopausal women (1, 6, 7). The shortterm follow-up in our study has confirmed aggressive behavior of breast cancer in younger people. Five (71%) of our seven patients who died from metastatic disease were premenopausal. Although the difference was not significant, a higher rate of LVI (+) tumours in younger patients has indicated tumour aggressiveness. Based on our results, the presence of LVI is not so significantly present according to menopausal status. Tumour size is the most powerful predictor of breast cancer for local recurrence, regional and systemic
286
G. Gurleyik et al. Table III Markers of prognosis in patients who died from metastatic disease Age/Menopause
Tumour size (cm)
Axillary status metastatic/total
Grade
Hormone receptor Status
LVI
67 post 48 pre 40 pre 40 pre 51 pre 65 post 45 pre
3 2 2 4 4 3 3
19/25 9/15 2/26 5/14 34/34 9/19 8/17
3 2 2 3 3 3 3
OR (-) PR (-)* OR (+) PR (+) OR (-) PR (-) OR (-) PR (-) OR (-) PR (-) OR (-) PR (-) OR (-) PR (-)
+ + + + + + +
*OR : Oestrogen receptor, PR : Progesterone receptor.
spread, and therefore for overall survival. There is a significant decrease in disease-free survival for patients with tumours greater than T1 (6, 8). Our findings have confirmed a higher rate of LVI (+) with greater tumour size. The observation of a gradual increase of positive LVI rate according to tumour size has supported the power of LVI for the prediction of a worse outcome. Another marker of aggressive behaviour of the tumour is the nuclear grade, which independently affects disease-free and overall survival (8). According to our results, LVI can also be accepted as a predictor of an aggressive tumour, in that the presence of LVI has increased up to 73% when the nuclear grade has been determined as 3, whereas there is no positive LVI in nuclear grade 1 tumours in our patients. NERI et al. (9) have also reported that the decision to apply adjuvant therapy should consider the presence of LVI as an indicator of high biological aggressiveness. The larger studies with a longer follow-up have demonstrated that patients with ER-positive tumours have longer disease-free intervals than patients with ERnegative tumours (7, 9). Although there was a small number of patients in our study, all patients (except one ; 86%) who died from invasive breast cancer had both ER and PR-negative tumours. We can comment that patients with hormone receptor negative tumours have a poorer prognosis ; therefore, LVI (+) can also confirm a worse outcome. A significantly lower LVI (+) rate in ER and PR positive tumours has supported the suggestion that the presence of LVI affects the differentiation status of the malignant cells. Axillary lymph node involvement is accepted as the most powerful marker of systemic disease and poorer prognosis that six of our seven patients died during follow-up had more than four involved nodes. Recent papers have reported that LVI has been found to be a significant predictor of serious axillary metastasis and poorer prognosis (10, 11). The presence of LVI has been significantly associated with both a shortened diseasefree interval and disease specific survival (12). When evaluating the relationship of LVI with axillary status,
our findings have supported the significance of LVI on the axillary involvement, in that the rate of LVI (+) has gradually increased with the number of involved lymph nodes. Axillary status represents a metastatic (systemic spreading) ability of primary breast malignancy. Our LVI results have also supported the predictive power of LVI concerning the potential of metastasis ; when axillary involvement progresses from negative to more than ten nodes, the rate of positive LVI increases from 14 to 100%. In recent studies, LVI was also found predictive of axillary involvement (13-15). SCHOPPMANN et al. (16) have reported that the determination of lymphatic microvessel density and LVI predicted high metastatic potential in breast cancer, and LVI was significantly associated with a higher risk for developing lymph node metastasis. Patients with negative axilla have a relatively better prognosis, but a small number (14%) of patients with positive LVI despite negative axilla possess a distinct importance. LVI is an adverse prognostic factor for local and distant relapse and disease-free and overall survival. Node negative patients with LVI are candidates for adjuvant therapy (6-8). We must take into account this group for adjuvant treatment based on the increased risk of aggressive behavior due to LVI. The Ludwig Breast Cancer Study Group studied the prognostic significance of LVI in a large number of patients. They found lower disease-free and overall survival in patients with peritumoural LVI (3). WOO et al. (2) followed up 1258 patients during 12 years for the significance of various factors in predicting survival. They suggested that patients with 0 to 3 lymph nodes and positive LVI may be candidates for aggressive adjuvant therapy. Positive LVI could likely be regarded as the precursor of nodal involvement. Adjuvant chemotheraphy is almost always recommended for large tumours and node positive cases, so the addition of LVI would have little effect on treatment recommendations. On the other hand, chemotherapy may be beneficial for small node negative tumours with positive LVI. LVI may be used for adjuvant treatment decisions especially in node negative patients. This hypothesis should be supported with additional studies.
LVI, Prognostic Marker for Breast Cancer Despite the relatively small number of patients and the short follow-up period, we conclude that a high rate of positive LVI shows a close relationship with poor prognostic markers in patients with invasive breast cancer. The presence of peritumoral LVI may be used as an indicator of biologically aggressive behaviour, of metastatic ability, and of a regional and systemic spreading risk of primary malignancy. Based on our findings we can comment that LVI has a close relationship with studied essential prognostic markers except menopausal status.
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7.
8. 9. 10. 11.
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