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Acta chir belg, 2007, 107, 284-287

Introduction
Prognostic factors can be used to predict the natural his-
tory 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 metasta-
tic involvement in axillary lymph nodes, tumour size,
nuclear grade, hormone receptor status, and patients age
are well known prognostic factors for patients with inva-
sive breast cancer. Lymph node involvement with the
tumour cells is accepted as the most powerful prognos-
tic 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 relation-
ship 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 dissec-
tion. The tumour size was measured macroscopically.
Nuclear grade was determined by a modification of the
simplified Black technique. Axillary status was evaluat-
ed 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 deter-
mined by immunohistochemistry. Tumour and peri-
tumoral 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
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 patients 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 stud-
ied 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 respec-
tively. 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 pres-
ence 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.
LVI, Prognostic Marker for Breast Cancer 285
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 Fishers 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 differ-
ence of LVI (+) was significant according to hormone
receptors status. The rate of LVI (+) has increased pro-
portionally 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
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 prog-
nostic factors in patients with invasive breast cancer for
determining the subgroup of patients who have biologi-
cally aggressive tumours. Axillary lymph node involve-
ment, younger age, high nuclear grade, large tumour
size and the absence of hormonal receptors were signif-
icantly 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 short-
term 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
Table I
The relationship of LVI with prognostic markers of breast
cancer
No of patients LVI (+)
(n = 81)
Pre 30 (37)* 17 (57)
Menopausal status p = 0.2491
Post 51 (63) 21 (41)
Positive 55 (68) 16 (29)
Oestrogen receptor p < 0.0001
Negative 26 (32) 22 (85)
Positive 51 (63) 16 (31)
Progesterone receptor
Negative 30 (27) 22 (73) p = 0.0004
Tumour size 0-2 cm 34 (42) 10 (29)
2-5 cm 41 (51) 22 (54) p = 0.028
> 5 cm 6 (7) 6 (100) p = 0.002
Nuclear grade 1 7 (9) 0
2 48 (51) 18 (38)
3 26 (32) 20 (77) p < 0.001
Axillary lymph node
Negative 36 (44) 5 (14)
Positive 45 (56) 33 (73) p < 0.0001
Positive 1-3 23 13 (57) p < 0.0001
Positive 4-9 15 13 (87) p < 0.0001
Positive > 10 7 7 (100) p < 0.0001
* Numbers in parentheses are percentages.
Table II
The rate of positive LVI according to markers
of poorer prognosis
Prognostic Markers Rate of positive LVI (%)
Grade 2 38
T2 54
Premenopausal 57
PR* negative 73
Axilla positive 73
Grade 3 77
OR* negative 85
Positive 4-9 nodes 87
T3 100
Positive > 10 nodes 100
Fatal metastatic disease 100
* OR : Oestrogen receptor, PR : Progesterone receptor.
286 G. Gurleyik et al.
spread, and therefore for overall survival. There is a sig-
nificant 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 indi-
cator 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 ER-
negative 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 disease-
free 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 micro-
vessel 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 adju-
vant 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 peritu-
moural 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 like-
ly be regarded as the precursor of nodal involvement.
Adjuvant chemotheraphy is almost always recommend-
ed 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.
Table III
Markers of prognosis in patients who died from metastatic disease
Age/Menopause Tumour size Axillary status Grade Hormone receptor LVI
(cm) metastatic/total Status
67 post 3 19/25 3 OR (-) PR (-)* +
48 pre 2 9/15 2 OR (+) PR (+) +
40 pre 2 2/26 2 OR (-) PR (-) +
40 pre 4 5/14 3 OR (-) PR (-) +
51 pre 4 34/34 3 OR (-) PR (-) +
65 post 3 9/19 3 OR (-) PR (-) +
45 pre 3 8/17 3 OR (-) PR (-) +
*OR : Oestrogen receptor, PR : Progesterone receptor.
LVI, Prognostic Marker for Breast Cancer 287
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 can-
cer. The presence of peritumoral LVI may be used as an
indicator of biologically aggressive behaviour, of
metastatic ability, and of a regional and systemic spread-
ing 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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Gunay Gurleyik
Eski Bagdat cad. 29/9
Altintepe 34840, Istanbul, Turkey
E-mail : ggurleyik@yahoo.com