The Accuracy of Combined Versus Largest

Diameter in Staging Multifocal Breast Cancer

Brendan J ODaly, MB, BCh, BAO, Karl J Sweeney, MD, AFRSCI, Paul F Ridgway, MD, AFRSCI,
Cecily Quinn, MD, FRCP, Enda WM McDermott, MCh, FRCS, Niall J OHiggins, MCh, FRCS, FACS(Hon),
Arnold DK Hill, MCh, FRCSI
Evaluating the size of multifocal breast cancer for staging purposes is problematic. Historically,
the largest tumor focus in isolation has been used to stage multifocal disease and determine
optimum adjuvant therapy. This study compared multifocal and unifocal breast cancer to
determine if multifocal breast cancer presents at a higher stage.
STUDY DESIGN: We performed a retrospective review of a prospectively collected database of 328 patients who
underwent sentinel lymph node biopsy over a 7-year period. Clinical presentation and histopathologic features of multifocal breast cancer were compared with those of unifocal disease.
RESULTS:
Fifty-three (16%) patients presented with multifocal disease. Higher tumor grade was observed in
the multifocal tumors compared with unifocal tumors (34% versus 20% grade III tumor, multifocal
versus unifocal disease; p 0.03). Use of combined tumor focus diameter upstaged (pT status) 18
(34%) patients with multifocal tumors. There was no difference in nodal positivity based on pT
status between largest and combined diameter multifocal disease.
CONCLUSIONS: Combined tumor diameter in multifocal breast cancer does not correspond with an increase in
sentinel node positivity and should not be used for staging purposes. (J Am Coll Surg 2007;204:
282285. 2007 by the American College of Surgeons)
BACKGROUND:

Primary tumor burden is an independent predictor of

metastatic disease in breast cancer.1 Preoperative radiologic diameter of unifocal breast cancer gives an estimate
of tumor burden and allows planning of the extent of
axillary surgery. Postoperative histologic assessment of
the size of the tumor is used to predict the risk of metastatic disease and the need for adjuvant systemic therapy.
Multifocal and multicentric tumors are defined by the
presence of two or more distinct foci of carcinoma in the
same breast. Multifocality represents the presence of multiple foci of the same tumor; multicentricity is defined as
multiple primary tumors in the same breast.2 In clinical
practice, the distinction is arbitrary; it can be difficult to
distinguish one from the other, even with molecular studies, and there is no difference in survival between patients
with multicentric and multifocal disease (MF).2

The American Joint Committee on Cancer and the

International Union Against Cancer (AJCC/UICC)
guidelines advocate using the diameter of the largest
tumor only in the staging of MF, although it has been
suggested that the incidence of lymph node metastases is
higher in MF staged by this method.3-6 A recent report
concluded that combined tumor size more accurately
predicted nodal involvement in MF.7
The aim of this study was to determine if multifocal
breast cancer presents at a higher stage than unifocal
breast cancer.
METHODS
Patients with multifocal breast cancer were identified retrospectively from a prospectively collected database of all patients who underwent sentinel lymph node (SLN) biopsy
for invasive breast carcinoma between 1998 and 2005. Patients identified for inclusion in this study had two or more
distinct invasive tumors in the same breast on histopathologic analysis. Exclusion criteria for this study included previous breast cancer, postneoadjuvant chemotherapy, or
clinically palpable axillary lymph node disease.
Completion axillary lymph node dissection was performed if the SLN was positive, or as part of another

Competing Interests Declared: None.

Received April 12, 2006; Revised October 31, 2006; Accepted November 8,
2006.
From the Departments of Surgery (ODaly, Sweeney, Ridgway, McDermott,
OHiggins, Hill); and Histopathology (Quinn), St Vincents University Hospital, Elm Park, Dublin, Ireland.
Correspondence address: Prof Arnold DK Hill, Department of Surgery,
RCSI, Beaumont Hospital, Dublin, Ireland.

2007 by the American College of Surgeons

Published by Elsevier Inc.

282

ISSN 1072-7515/07/$32.00
doi:10.1016/j.jamcollsurg.2006.11.005

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Tumor Diameter in Staging Mulitifocal Breast Cancer

283

Table 1. Tumor Characteristics

Characteristics

Unifocal (n 275 patients)

Multifocal (n 53 patients)

p Value

1 (0)

2.2 (0.5)

NA

275 (100)
NA
NA
NA

NA
43 (81)
8 (15)
2 (4)

NA

1.8 (1.1)
NA
NA
NA
1.8 (1.1)

1.8 (1.0)
0.8 (0.5)
0.5 (0.4)
0.7 (0.4)
2.5 (1.4)

NA

89 (32)
132 (48)
54 (20)

10 (19)
25 (47)
18 (34)

0.03

207 (75)
29 (11)
39 (14)
195 (71)
244 (89)
113 (41)
77 (28)
138 (50)
38 (14)

34 (64)
12 (23)
7 (13)
37 (70)
44 (83)
20 (38)
18 (34)
28 (53)
9 (17)

0.05

Mean No of foci (SD)

Tumor foci, n (%)
1
2
3
4
Focus size, cm, mean (SD)
Largest
Second
Third
Fourth
Cumulative size, cm, mean (SD)
Grade, n (%)
I
II
III
Type, n (%)
Invasive ductal carcinoma
Invasive lobular carcinoma
Other
Associated ductal carcinoma in situ, n (%)
Estrogen receptor positive, n (%)
Lymphovascular invasion present, n (%)
SLN positive, n (%)
ALND performed, n (%)
Non-SLN positive, n (%)

0.01*

0.87
0.25
0.76
0.41
0.77
0.53

*Students t-test.

Chi-square test.

Fishers exact test.

ALND, axillary lymph node dissection; SLN, sentinel lymph node.

clinical trial protocol. Additionally, the first 70 sentinel

node biopsies performed were validated by a completion
axillary clearance; mandatory completion axillary clearance was discontinued only after at least 20 sentinel
node biopsies had been performed by each surgeon with
no false negatives.
The database contains information about tumor type,
grade, size (dominant focus versus combined foci), estrogen receptor status, presence of lymphovascular invasion, and presence of associated ductal or lobular carcinoma in situ. The sentinel node was identified by a
combination of lymphoscintigraphy, blue dye, and an
intraoperative hand-held gamma probe (Neoprobe
2000). All lymph nodes were examined by hematoxylin
and eosin and immunohistologic (cytokeratin) staining
(CAM 5.2 antibody).
Data are presented as mean and standard deviation
unless otherwise stated. Students t-test was used to com-

pare patient ages and tumor sizes and to compare tumor

sizes between patients with positive and negative axillary
nodes. Mann-Whitney U test was used to compare total
nodal positivity. Chi-square test was used to compare
tumor grade, histologic subtype, and to compare nodal
disease based on pT status. Fishers exact test was used
for all other analyses. A p value less than 0.05 was considered statistically significant.
RESULTS
Between 1999 and 2004, 328 patients underwent SLN
biopsy. Of these, 53 patients (16%) had MF invasive breast
cancer. There was no significant difference in the mean age
in years (SD) of the patients with unifocal or MF breast
cancer (57 9.7 years versus 56 8.0 years, respectively).
Unifocal and MF breast cancers were similar in histologic
type, in situ component, and estrogen status (Table 1).
Multifocality was associated with a higher grade of tumor.

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ODaly et al

Tumor Diameter in Staging Mulitifocal Breast Cancer

Table 2. Mean Tumor Size and Tumor Classification Distribution in Multifocal Versus Unifocal Invasive Tumors

Classification

Multifocal (n 53)
Dominant
Combined
focus
foci

Unifocal
(n 275)

Tumor size, cm,

mean (SD)
pT1, n (%)
pT1a
pT1b
pT1c
pT2, n (%)
pT3, n (%)

1.8 (0.9)
39 (74)
0 (0)
11 (21)
28 (53)
13 (25)
1 (2)

1.8 (1.1)
194 (71)
16 (6)
51 (19)
129 (47)
76 (28)
5 (2)

2.5 (1.4)*
27 (51)
0 (0)
4 (8)
23 (43)
22 (42)
4 (8)

pT1, 2 cm (pT1a 0.5 cm, pT1b 0.51 cm, pT1c 12 cm); pT2,
2 cm5 cm; pT3, 5 cm.
*p 0.01 versus largest focus and unifocal disease; Students t-test.

p 0.005 versus unifocal disease; chi-square test.

There was no significant difference in sentinel node

positivity between unifocal and MF breast cancer, and
both types had similar nonsentinel node disease burden
(Table 1). Axillary lymph node disease was associated
with larger unifocal cancers (2.5 1.3 cm versus
1.6 1.0 cm; p 0.0001), largest focus of multifocal
cancer (2.2 1.3 cm versus 1.5 0.6 cm; p 0.007),
and larger combined foci of breast cancer (3.2 1.7 cm
versus 2.0 0.9 cm; p 0.001). Two patients in the
MF group and one in the unifocal group had a falsenegative SLN biopsy. Both of these occurred during validation of the sentinel node biopsy technique.
The largest focus of tumor in MF disease was equivalent in size to that of the unifocal tumors. The combined diameters of MF tumors resulted in a larger mean
tumor size compared with the largest focus and the size
of the unifocal lesions (Table 2). Staging of MF disease
according to the TNM classification using the dominant
focus resulted in a similar distribution of patients by pT
status as in the unifocal group. Eighteen patients were
upstaged when MF disease was staged according to combined foci size: 7 patients were upstaged from pT1b to
pT1c; 8 patients were upstaged from pT1c to pT2; 1
patient was upstaged from pT1c to pT3; and 2 patients
were upstaged from pT2 to pT3. There was no difference in the numbers of patients with nodal disease when
using largest or combined foci size (pT1, 14 versus 9;
pT2, 7 versus 9; pT3, 1 versus 5; p 0.2).
DISCUSSION
The incidence of multifocality in breast cancer varies
from 13% to 70%, and it is an important issue in patient
treatment with the advent of increasing imaging accu-

J Am Coll Surg

racy, the use of sentinel node biopsy, and breastconserving surgery.4,8 Evaluating the size of MF breast
carcinomas for staging purposes is a problem. Current
practice uses the diameter of the largest focus to stage the
disease, because it has been suggested that combined
tumor diameter tends to overestimate the volume and
consequently reduce the prognosis of patients.5
In this study, MF tumors had a different distribution
within pT classifications depending on the method used
to estimate tumor size, particularly, an increase from
pT1 to pT2 tumors using combined foci diameters. Although there was a correlation between tumor size and
nodal disease, this was observed using both the largest
focus and the combined size. This suggests that the metastatic potential and, ultimately, prognosis are not dependent on the combined volume of tumor in multifocal disease, but may be predicted according to the
American Joint Committee on Cancer guidelines.
With larger numbers, differences in nodal burden between combined and largest focus size may become apparent. In a series of 101 invasive MF tumors, the odds
ratio of positive lymph node status in multifocal versus
unifocal cases was 2.8 using largest diameter as a tumor
size estimate (p 0.0001). But when the combined diameter assessment was used, the frequency of lymph
node positivity was not significantly different in multifocal versus unifocal cases of the same size.6
We observed that MF breast cancer was associated
with a similar incidence of SLN positivity as was unifocal disease. The success rate, sensitivity, and falsenegative rate of SLN biopsy in MF disease was comparable with that observed for unifocal disease.9 Other
authors have reported similar success in correctly identifying MF lesions.10 SLN biopsy has attained definitive
value in surgical management of MF breast cancer, and
multifocality should not be a contraindication to SLN
biopsy.
In contrast to previous reports, the average tumor
grade of the MF group in this series was higher than that
in the unifocal group, conferring poorer outcomes and
increasing the need for systemic therapy.5,7,11 This has
implications for therapeutic planning for these patients,
and multifocality may be an indication for neoadjuvant
chemotherapy.
In conclusion, the use of largest diameter focus as the
pT status of multifocal breast cancer is appropriate, because combined measurements are not associated with
increased nodal disease, as would be observed in unifocal

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ODaly et al

staging. Clinical decision making about optimum adjuvant treatment in MF breast cancer should continue to
be based on the largest focus rather than on combined
foci diameter. Longterm prospective trials are needed to
provide rational treatment guidelines for management
of patients with MF disease.
Author Contributions

Study conception and design: ODaly, Sweeney, Ridgway, Quinn, McDermott, OHiggins, Hill
Acquisition of data: ODaly
Analysis and interpretation of data: ODaly, Sweeney
Drafting of manuscript: ODaly, Sweeney
Critical revision: ODaly, Sweeney, Ridgway, Quinn,
McDermott, OHiggins, Hill
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