Increased Lymph Node Positivity in

Multifocal and Multicentric Breast Cancer

Neslihan Cabioglu, MD, PhD, Vahit Ozmen, MD, FACS, Hakan Kaya, MD, Stk Tuzlali, MD,
Abdullah Igci, MD, Mahmut Muslumanoglu, MD, Mustafa Kecer, MD, Temel Dagoglu, MD
Multifocal and multicentric (MF/MC) breast cancers have been reported to be associated with
increased lymph node metastases. The limited data on this issue prompted us to investigate the
pathologic and clinical differences between unifocal and MF/MC breast cancer.
STUDY DESIGN: Between 1990 and 2002, 1,322 patients with operable invasive breast cancer underwent a
definitive operation at our Breast Clinic. Patients with MF/MC breast cancer (n 147, 11%)
were compared with patients with unifocal breast cancer (n 1,175; 89%) in terms of pathologic and clinical characteristics.
RESULTS:
Patients with MF/MC were found to have a higher frequency of lymph node metastases when
the largest diameter was used as a tumor size estimate for MF/MC cancer (unifocal T1 and T2,
35% and 49%, respectively, versus MF/MC T1 and T2, 48% and 67%, respectively; p 0.05
and p 0.003, respectively). When the combined diameter assessment was used, the frequency
of lymph node positivity was similarly higher in MF/MC patients versus unifocal patients
(unifocal T1 and T2, 35% and 49%, respectively, versus MF/MC T1 and T2, 49% and 61%,
respectively; p 0.08 and p 0.046, respectively). At a median followup of 55 months (range
12 to 153 months), 5-year disease-free survival (DFS; unifocal, 88% versus MF/MC, 82%,
p 0.14) and overall survival (OS) rates (unifocal, 92% versus MF/MC, 93%, p 0.43) did
not show any significant difference between two groups.
CONCLUSIONS: Our data suggest that breast tumors with multiple foci have a different biology, with an
increased metastatic potential to axillary lymph nodes, regardless of tumor size, that reflects an
advanced stage. The clinical relevance of the currently used TNM classification system, which
uses the diameter of the largest nodule, is supported by our findings. (J Am Coll Surg 2009;208:
6774. 2008 by the American College of Surgeons)
BACKGROUND:

Tumor size is a strong prognostic factor in breast cancer as

one of the main parameters in staging of the disease1 and
also as an important predictor of axillary lymph node metastases.2 In unifocal breast cancer, the largest diameter of
the invasive tumor has been considered in staging of patients. Multifocal or multicentric (MF/MC) tumors are
defined by the presence of simultaneous independent multiple infiltrating and macroscopically measurable tumors in
the same breast.1 Practically, the distinction between mul-

tifocality and multicentricity is based on topographic anatomy. Multifocality is defined by the presence of multiple
foci in the same quadrant of the same breast; multicentricity involves the occurrence of separate tumors at a distance
of at least 5 cm in different quadrants.3
For the staging of MF/MC breast cancers, the American Joint Committee on Cancer (AJCC)1 recommends
using the diameter of the largest tumor only. But
MF/MC tumors have been found to be associated with
increased lymph node involvement compared with unifocal tumors,4-13 despite some conflicting data.14 It is
still controversial whether this reflects a larger tumor
load10 or a different biologic behavior. In addition, there
are also conflicting reports about the effect of MF/MC
breast cancers on patient outcomes compared with unifocal breast cancers.6,15 So, the limited data on this issue
prompted us to investigate the pathologic and clinical
differences, including lymph node involvement and
outcomes, between unifocal and MF/MC breast cancer.

Disclosure Information: Nothing to disclose.

Abstract presented at the 27th Annual Meeting of the San Antonio Breast
Cancer Symposium, San Antonio, TX, 2004.
Received April 9, 2008; Revised August 28, 2008; Accepted September 2,
2008.
From the Departments of Surgery (Cabioglu, Ozmen, Kaya, Igci, Muslumanoglu, Kecer, Dagoglu) and Pathology (Tuzlali), Istanbul Medical Faculty,
University of Istanbul, Istanbul, Turkey.
Correspondence address: Neslihan Cabioglu, MD, PhD, Istanbul Medical
Faculty, University of Istanbul, Zeytinlik mah. Odabasi sok. No: 47/10. Bakiroy, Istanbul, Turkey.

2008 by the American College of Surgeons

Published by Elsevier Inc.

67

ISSN 1072-7515/09/$36.00
doi:10.1016/j.jamcollsurg.2008.09.001

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Multifocal and Multicentric Breast Cancer

Abbreviations and Acronyms

DFS
disease-free survival
H&E
hematoxylin and eosin
MF/MC multifocal and multicentric

METHODS
A retrospective medical chart review was performed in patients diagnosed with invasive breast cancer who underwent surgery at our Breast Clinic between January 1990
and January 2002. The patient list was generated by searching the medical records of patients who had primary tumor
excision (excisional biopsy or segmental mastectomy) or
mastectomy with axillary lymph node dissection. Patients
diagnosed with T1 to T3 invasive breast cancer (n 1,322)
were included in the study, and patients treated with neoadjuvant chemotherapy were excluded (n 210). Patients
who underwent sentinel lymph node biopsy between
March 1998 and January 2002 (n 152) were also included into the study. But sentinel lymph node biopsy was
followed immediately by axillary lymph node dissection
that removed all nodes in levels I and II, regardless of positivity of the sentinel nodes, as part of a prospective trial at
our institution during the study period.16
Between 1990 and 2002, ultrasonography or mammography, or both, of the breast were routinely used as preoperative imaging modalities to determine the extent of the
tumor (unifocal versus multifocal or multicentric tumor)
to plan the most appropriate surgical procedure for the
patients, ie, whether breast conservation or mastectomy
should be performed. The following data were obtained
from the medical records: age, definitive surgical procedure
performed (mastectomy or breast-conserving surgery), tumor characteristics (tumor size, nuclear and histologic
grade, histologic type, presence of lymphovascular invasion, status of estrogen and progesterone receptors, presence of multifocality or multicentricity), nodal status,
stage, type of adjuvant treatment including chemotherapy,
radiotherapy and hormonal treatment, followup time, and
occurrence of local and systemic recurrences or deaths. The
6th edition of the American Joint Committee on Cancer
Staging Manual was used in breast cancer staging.1
Pathologic evaluation

The definition of multifocality or multicentricity was

based on the presence of simultaneous multiple macroscopically separated tumors in the same breast. Multifocality was defined as the presence of at least two foci of invasive cancer 5 mm apart, located in the same quadrant
within a biopsy specimen 5 cm in its maximum dimen-

J Am Coll Surg

sion. Random sections from suspicious areas were performed per quadrant in the lumpectomy or mastectomy
specimen to explore any possible additional foci. All axillary lymph nodes were pathologically evaluated to determine nodal status. For patients having sentinel lymph node
biopsy, at least four sections were obtained from each block
of sentinel node in a different level (100 to 500 m apart)
and stained with hematoxylin and eosin (H&E). Up to 10
additional sections stained with H&E were examined in
patients with negative sentinel lymph nodes. Detection of
metastases in sentinel lymph nodes were based on the results obtained by H&E staining in paraffin-embedded sections.16 A micrometastasis was considered as a lymph node
metastasis 2 mm, but 0.2 mm in size; a macrometastasis was defined as a lymph node metastasis 2 mm.1
Nonsentinel lymph nodes were fixed in formalin, sectioned
(approximately four sections per lymph node), and evaluated by H&E staining. Estrogen and progesterone receptor
status were determined by immunohistochemical staining.
Followup

Patients were followed up with history and physical examination at least every 3 to 4 months for the first 2 years,
every 6 months for the next 3 years, and annually thereafter, if they were free of disease. Mammograms of the breast
along with ultrasonography, chest x-ray, liver ultrasonography, bone scintigram, and biochemical screening were obtained once a year in patients with high likelihood of recurrence. MRI was also obtained for some patients with dense
breasts or suspicious lesions in the breast in conventional
imaging techniques. Locoregional and distant relapses were
diagnosed by imaging techniques, biopsy, or both.
Data analysis and statistical methods

For each patient with MF/MC breast cancer, two different

tumor size estimates were considered: the diameter of the
largest tumor nodule (T index) and the sum of the diameters of all tumor nodules present in the breast (T cumulative). Patients with MF/MC breast cancer were compared
with patients with unifocal breast cancer in terms of pathologic and clinical characteristics.
The SPSS 10.1 software package (SPSS Inc) was used
for statistical analyses. Categorical variables were evaluated by the two-tailed Fishers exact test; continuous
variables were compared by using the Students t-test.
Factors that were significantly associated with lymph
node metastasis were evaluated by multivariable logistic
regression analysis. Disease-free survival (DFS) time was
considered as the interval between the date of first diagnosis
of the tumor and the date of the first documented evidence of
new disease manifestation in locoregional or distant sites, or
the date of last followup if no new disease was detected. Over-

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Table 1. Demographic and Pathologic Characteristics of Patients with Unifocal and Multifocal or Multicentric Breast
Cancer

Variables

Patients
with unifocal
breast cancer
(n 1,175)

Age, y, median (range)

50 (2190)
Histology, n
1,174
Invasive ductal, n (%)
829 (70)
Other, n (%)
345 (30)
Invasive lobular, n (%)
80 (7)
Other, n (%)
1,094 (93)
Nuclear grade, n
1,024
Well differentiated,
n (%)
31 (3)
Intermediate, n (%)
633 (62)
Poorly differentiated,
n (%)
360 (35)
Histologic grade, n
1,011
Well differentiated,
n (%)
34 (3)
Intermediate, n (%)
495 (49)
Poorly differentiated,
n (%)
482 (48)
Lymphovascular
invasion, n
1,175
Positive, n (%)
384 (33)
Negative, n (%)
791 (67)
Estrogen receptor, n
1,175
Positive, n (%)
712 (61)
Negative, n (%)
463 (39)
Progesterone receptor,
n
1,175
Positive, n (%)
547 (47)
Negative, n (%)
628 (53)

Patients with
multifocal/
multicentric
breast cancer
(n 147)

48 (2797)
147
89 (60)
58 (40)
17 (12)
130 (88)
135
3 (2)
80 (59)

p
Value*

0.08
0.017
0.044

0.39

52 (39)
132
3 (2)
73 (55)

0.42

56 (43)
147
51 (35)
96 (65)
147
98 (67)
49 (33)
147
75 (51)
72 (49)

0.64

0.18

0.18

*Students t-test was used for comparing continuous variables (age), and
Fishers exact test was used for comparing all the other categorical variables.
Missing cases were excluded from the analyses.

all survival time was defined as the interval between the first
diagnosis of the tumor and the date of the last followup or
death. Survival curves were estimated using the Kaplan-Meier
method. The Kaplan-Meier survival curves were compared
using the log-rank test. A p value 0.05 was considered
statistically significant.

RESULTS
Patient and tumor characteristics are shown in Tables 1 and 2.
Among 1,322 patients in the study, 147 patients (11%)
were identified as patients with MF/MC breast cancer. The
median ages of patients with unifocal and MF/MC breast
cancer were 50 years (range 21 to 90 years) and 48 years

Multifocal and Multicentric Breast Cancer

69

(range 27 to 97 years), respectively. Unifocal cancers were

more likely to be invasive ductal carcinomas; MF/MC cancers were more likely to be invasive lobular carcinomas
(Table 1). But no statistically significant differences could
be found between the two groups when patients with
unifocal and MF/MC breast cancer were compared in
regard to age, nuclear grade, histologic grade, lymphovascular invasion, and estrogen and progesterone receptor status (Table 1).
T1 (45% versus 43.5%), T2 (52.5% versus 55.1%), and
T3 (2.5% versus 1.4%) tumors were detected in similar
frequencies in unifocal and MF/MC breast cancers, respectively (Table 2). But patients with MF/MC tumors had a
higher frequency of lymph node metastases when T index
was used as a tumor size estimate for MF/MC breast cancer
(unifocal T1 and T2, 35% and 49%, respectively, versus
MF/MC T1 and T2, 48% and 67%, respectively; p 0.05
and p 0.003, respectively, Table 2). In addition, patients
with MF/MC were more likely to have four or more lymph
node metastases (N2/N3) presenting with stage III disease
(unifocal, 13% versus MF/MC, 23%, p 0.002). When
T cumulative was considered as a tumor size estimate for
MF/MC breast cancer, the frequency of lymph node positivity was similarly higher in MF/MC breast cancer versus
unifocal breast cancer (unifocal T1 and T2, 35% and 49%,
respectively, versus MF/MC T1 and T2, 49% and 61%,
respectively; p 0.08 and p 0.046, respectively, Table
2) even though the difference between the frequencies of
lymph node positivity in patients with unifocal T1 versus
MF/MC T1 did not reach the statistical significance.
Factors associated with lymph node positivity were also
investigated in this series. In univariate analysis, patients
with tumor size 2 cm, or with MF/MC tumors, or with
lymphovascular invasion positivity, or progesterone receptor negativity were more likely to have lymph node metastases compared with patients with tumor size 2 cm, or
with unifocal tumors, or with lymphovascular negativity,
or progesterone receptor positivity, respectively (Table 3).
Interestingly, no statistical difference could be found in
lymph node positivity between patients with invasive ductal cancer (44%) and invasive lobular cancer (39%;
p 0.39). When factors found to be statistically significant in univariate analyses were evaluated in a multivariable
logistic regression model, all factors including tumor
size 2 cm, presence of multifocality or multicentricity,
lymphovascular invasion positivity, or progesterone receptor negativity were found as significant independent factors
associated with lymph node involvement (Table 4).
Treatment

Patients with MF/MC tumors were more likely to have modified radical mastectomy (unifocal, 58% versus multifocal

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Multifocal and Multicentric Breast Cancer

J Am Coll Surg

Table 2. Pathologic Characteristics of Patients with Unifocal and Multifocal or Multicentric Breast Cancer
Patients with
multifocal/
multicentric
breast cancer
(n 147)

Patients
with unifocal
breast cancer
(n 1,175)
Variables

Pathologic tumor
size
T1
T2
T3
Axillary lymph node
involvement
Positive
Negative
Involved lymph
nodes, n
4
Other
Stage
I (n 375)
II (n 757)
III (n 190)
Lymph node
positivity
T1 index
T2 index
T3 index
Lymph node
positivity
T1 cumulative
T2 cumulative
T3 cumulative

p Value

529
617
29

45
52.5
2.5

64
81
2

43.5
55.1
1.4

493
682

42
58

86
61

58.5
41.5

153
1,022

13
87

34
113

342
677
156

29
58
13

33
80
34

187/529
302/617
4/29

35
49
14

31/64
54/81
1/2

48
67
50

0.050
0.003
0.30

187/529
302/617
4/29

35
49
14

22/45
50/82
14/20

49
61
70

0.08
0.046
0.001

0.94

0.0001

0.002
23
77
0.007
22.5
54.5
23

Fishers exact test was used for comparing all categorical variables.

80%; p 0.0001). In addition, patients with MF/MC breast

cancer were more likely to receive postmastectomy radiation
and chemotherapy compared with patients with unifocal
breast cancer. Based on their similar hormone receptor positivity, no difference could be found between patients with
unifocal and MF/MC breast cancer in regard to hormonal
treatment including tamoxifen (Table 5).
Outcomes

Median followup overall was 55 months (range 12 to

153 months). Median followup was 56 months (range 12
to 153 months) for unifocal patients, and 48 months
(range 13 to 145 months) for MF/MC patients. No significant differences could be found between systemic (unifocal, 7.7% versus MF/MC, 8.8%; p 0.62) and local recurrence rates (unifocal, 3.7% versus MF/MC, 5.4%;
p 0.36). A subgroup analysis of patients with breast con-

servation and multifocal tumors (n 30) revealed a local

recurrence rate (6.7%, MF/MC, versus 5.4%, unifocal;
p 0.68) similar to that for patients with unifocal cancers
(n 498) during the followup time frame of this study
(Table 6). Nevertheless, in the mastectomy group, patients
with MF/MC cancers (n 117) had a higher rate of chest
wall recurrence compared with patients with unifocal cancer (n 677); this difference, however, did not reach statistical significance (MF/MC, 5.1%, versus unifocal, 2.5;
p 0.13).
Five-year disease-free (unifocal, 88% versus MF/MC,
82%; p 0.14) and overall survival rates (unifocal, 92%
MF/MC, 93%; p 0.43) did not show any significant
difference between the two groups (Fig. 1). But in subgroup analysis, patients with stage I unifocal breast cancer
had improved 5-year DFS rates compared with stage I
MF/MC breast cancer patients (unifocal, 93% versus

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Cabioglu et al

Table 3. Factors Associated with Lymph Node Positivity in

Patients with Unifocal and Multifocal or Multicentric Breast
Cancer

Variables

Age, y
50
50
Tumor size
T1 ( 2 cm)
T2 and T3
Multifocality/multicentricity
Yes
No (unifocal)
Histopathology
Invasive ductal
Invasive lobular
Other
Lymphovascular invasion
Yes
No
Histologic grade
Well and intermediate
differentiated
Poorly differentiated
Nuclear grade
Well and intermediate
differentiated
Poorly differentiated
Estrogen receptor
Positive
Negative
Progesterone receptor
Negative
Positive

Lymph node
positivity
n
%

p Value

44
44
0.0001

218/593
361/729

37
50

86/147
493/1,175

59
42

0.0001

0.56
402/918
38/97
139/306

44
39
45

237/435
342/887

55
39

0.0001

0.48
273/605
255/538

45
47
0.30

335/747
198/412

45
48

347/810
232/512

43
45

330/700
249/622

47
40

0.39

0.01

Fishers exact test was used for comparing all the other categorical variables.

MF/MC, 80%; p 0.002; Fig. 2). Additional subgroup

analysis showed that patients with stage I unifocal breast
cancer had an improved 5-year distant metastasis-free survival
rate compared with stage I MF/MC breast cancer patients
(unifocal, 95% versus MF/MC, 83%; p 0.003); no statistical difference could be found in 5-year local recurrence-free
survival rates (unifocal, 96% versus MF/MC, 97%;
p 0.84).

DISCUSSION
The incidence of multifocal or multicentric tumors varies
from 10% to 70% in reported series depending on the
definition, sampling methods, and use of imaging techniques.11,17,18 Similar to Coombs and Boyages,11 we found

71

Table 4. Multivariable Logistic Regression Analysis for Factors Associated with Lymph Node Positivity in Patients with
Unifocal and Multifocal or Multicentric Breast Cancer
Variables

0.99
311/710
268/612

Multifocal and Multicentric Breast Cancer

Tumor size
T2 and T3 versus T1
Lymphovascular invasion
Yes versus no
Multifocality and multicentricity
Yes versus no
Progesterone receptor positivity
Yes versus no

Odds
ratio

95% CI for
odds ratio

p Value

1.61

1.282.01

0.0001

1.95

1.542.48

0.0001

2.00

1.402.86

0.0001

1.45

1.161.82

0.001

that 11% of patients with operable breast cancer in our

series had MF/MC breast cancer by using ultrasonography
or mammography, or both, as imaging techniques. Using
current approaches such as MRI along with conventional
imaging might result in an increased rate of detection of
multifocal or multicentric disease. A recent systematic review and metaanalysis from 19 studies19 showed that MRI
detects additional disease in 16% of patients with breast
cancer (n 2,610). In the sixth edition of the American
Joint Committee on Cancer Staging Manual,1 for multiple,
simultaneous, ipsilateral, primary, infiltrating, macroscopically measurable carcinomas, the largest primary carcinoma was used to designate T classification. Although a
separate T classification for smaller tumors was not assigned, it is important to note that this is a case of multiple,
simultaneous, ipsilateral, primary carcinomas so that the
outcomes of such patients should be analyzed separately in
the future. Based on this definition, we included in our
study only multiple invasive cancers in the same breast that
might result in a lower incidence of MF/MC breast cancer.
In concordance with previous reports, this study also
demonstrated that MF/MC breast cancer has a higher incidence of lymph node positivity than unifocal breast
cancer.4-13 The underlying biology, however, still remains
unclear. One of the proposed theories is this difference in
behavior might be from the aggressiveness of MF/MC tumors. But our data, with those from previous studies, could
not show any difference in the nuclear or histologic grades
or expression of hormone receptors (estrogen receptors or
progesterone receptors) of the tumors between unifocal
and MF/MC tumors. The only differences were the findings of higher frequencies of invasive lobular carcinoma
and lower frequencies of invasive ductal carcinoma in
MF/MC breast cancer compared with unifocal cancers, in
agreement with the studies of Vlastos and colleagues6 and
ODaly and associates.14 Another proposed theory is that
the increased lymph node positivity in MF/MC breast cancer might be from the larger tumor size when the sum of the

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Multifocal and Multicentric Breast Cancer

J Am Coll Surg

Table 5. Treatment Characteristics of Patients with Unifocal and Multifocal or Multicentric Breast Cancer

Variables

Operation
Breast conservation
Mastectomy
Postmastectomy radiation
Yes
No
Chemotherapy
Yes
No
Tamoxifen
Yes
No

Patients with unifocal

breast cancer
n
%

Patients with multifocal/

multicentric breast cancer
n
%

p Value

0.0001
498/1,175
677/1,175

42
58

30/147
117/147

20
80

306/623
317/623

49
51

77/113
36/113

68
32

654/1,072
418/1,072

61
39

95/137
42/137

69
31

683/1,062
389/1,062

64
36

93/137
44/137

68
32

0.0001

0.062

0.39

Missing cases were excluded from the analyses.

tumor foci was considered as the diameter of the tumor.

This theory has been supported by several studies that
showed that multifocality or multicentricity were no longer
associated with lymph node positivity when the combined
diameter assessment was used.7,11 But, our study, along
with the study by Andea and coworkers,10 indicated that
when either the largest diameter or the combined diameter
of the MF/MC tumor was used as the size of the tumor,
patients with MF/MC breast cancer were more likely to
have lymph node positivity. In addition, we also demonstrated that MF/MC tumors were associated with more
advanced stages of breast cancer based on the increased
number of involved lymph nodes (more than four) that is a
reflection of stage III disease according to the 6th edition of
the TNM classification in breast cancer staging, consistent
with the study by Vlastos and colleagues.6 So MF/MC

breast cancers have a different biology compared with unifocal

breast cancer, with a propensity to metastasize to lymph nodes
at smaller volumes irrespective of their tumor load, grade,
histologic type, or hormone receptor status. This observation
warrants additional investigation in future studies.
In this study, we analyzed factors associated with lymph
node positivity in our series. In agreement with previous
studies,2,12,13 we found that patients with bigger tumor size
and lymphovascular invasion were more likely to have
lymph node positivity compared with others. Our findings
also showed that presence of multifocality or multicentricity was an independent predictive factor of lymph node
metastasis, in concordance with the study of Arisio and
associates.13 But there are some conflicting data about progesterone receptor status. We demonstrated a positive relationship between progesterone receptor negativity and

Table 6. Outcomes of Patients with Unifocal and Multifocal or Multicentric Breast Cancer
Variables

Median followup time, mo (range)

Local recurrence, n (%)
After breast conservation, n (%)
After mastectomy, n (%)
Distant metastases, n (%)
5-y Overall disease-free survival, %*
Stage I
Stage II
Stage III
5-y Overall survival, %*
Stage I
Stage II
Stage III
*Kaplan-Meier estimates.

Patients with unifocal breast

cancer, (n 1,175)

Patients with multifocal/multicentric breast

cancer, (n 147)

p Value*

56 (12153)
44/1,175 (3.7)
27/498 (5.4)
17/677 (2.5)
90/1,175 (7.7)
88
93
87
83
92
95
92
83

48 (13145)
8/147 (5.4)
2/30 (6.7)
6/117 (5.1)
13/147 (8.8)
82
80
85
80
93
93
96
84

0.22
0.36
0.68
0.13
0.62
0.14
0.002
0.68
0.48
0.43
0.71
0.18
0.78

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73

Figure 2. Patients with stage I unifocal breast cancer had an improved disease-free survival rate compared with stage I multifocal/
multicentric breast cancer patients (5-year disease-free survival rates,
unifocal, 93% versus 80% for multifocal/multicentric; p 0.002). Dotted line, multifocal/multicentric; solid line, unifocal.

Figure 1. (A) Disease-free survival rates of all patients (5-year diseasefree survival rates, for unifocal, 88% versus 82% for multifocal/
multicentric; p 0.14). (B) Five-year overall survival rates of all
patients (unifocal, 92% versus 93% for multifocal/multicentric,
p 0.43) did not show any significant difference between the two
groups. Dotted line, multifocal/multicentric; solid line, unifocal.

lymph node involvement, similar to the findings of Silverstein and coauthors,2 even though Arisio and colleagues13
could not find an association between lymph node positivity and progesterone receptor negativity. In addition, we
also could not demonstrate any significant difference between patients with invasive ductal carcinoma and invasive
lobular carcinoma in regard to lymph node positivity, sim-

ilar to results of Silverstein and associates.2 So, the increased

lymph node positivity in MF/MC breast cancers may not
be from the higher likelihood of invasive lobular type histology in MF/MC patients compared with that in patients
with unifocal breast cancer.
There are conflicting data about the influence of
MF/MC tumors on outcomes of patients with breast cancer.6,15,20 In our study, MF/MC breast cancer was associated
with more advanced stages of breast cancer that resulted in
more aggressive therapy in these patients. So, patients in
our series were more likely to receive chemotherapy and
postmastectomy irradiation. But when patients were tabulated according to the stage in each group, no difference
could be found between patients with unifocal or MF/MC
breast cancer in terms of rates of systemic metastases, local
recurrences, DFS, or overall survival. These findings are
consistent with those from previous reports,6,20 except in
patients with stage I MF/MC disease, who showed a poorer
DFS along with distant metastasis-free survival than patients with unifocal breast cancer. This finding might be
associated with the aggressiveness of the small MF/MC
tumors despite lymph node negativity. But it is intriguing
why this aggressive behavior of small lymph-node negative
MF/MC breast cancers did not translate into poor overall
survival. Patients with breast conservation in both unifocal
and MF/MC groups in our series showed a similar local
recurrence rate (unifocal, 5.4% versus MF/MC, 6.7%)
during a 5-year followup period. This finding agrees with
results of previous studies indicating the safety of perform-

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Multifocal and Multicentric Breast Cancer

ing breast-conserving surgery in patients with multiple

tumors.20-26 But patients with MF/MC tumors in the mastectomy group revealed a higher incidence of chest wall
recurrence, suggesting that multicentricity is an additional
risk factor along with lymph node status for locoregional
recurrence, influencing the decision on whether to do postmastectomy irradiation.27
In conclusion, our data suggest that breast tumors with
multiple foci have a different biology, with an increased
metastatic potential to axillary lymph nodes, regardless of
tumor size that reflects an advanced stage. But our data
could not show any difference in overall survival between
patients with MF/MC breast cancer and patients with unifocal breast cancer. So, the clinical relevance of the currently used TNM classification system, which uses the diameter of the largest nodule, is supported by our findings.
Because patients with stage I MF/MC disease had poorer DFS
rates than patients with unifocal cancers, this finding should
be investigated in larger patient populations.
Author Contributions
Study conception and design: Cabioglu, Ozmen
Acquisition of data: Kaya
Analysis and interpretation of data: Cabioglu, Ozmen
Drafting of manuscript: Cabioglu
Critical revision: Tuzlali, Igci, Muslumanoglu, Kecer, Dagoglu

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