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ORIGINAL ARTICLE
MR Imaging Features of Triple-Negative Breast Cancers
Janice S. Sung, MD,* Maxine S. Jochelson, MD,* Sandra Brennan, MD,*
Sandra Joo, MD,† Yong H. Wen, MD, PhD,‡ Chaya Moskowitz, PhD,§
Junting Zheng, MS,§ D David Dershaw, MD,* and Elizabeth A. Morris, MD*
*Department of Radiology, àDepartment of Pathology and §Department of Epidemiology and
Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, New York; †Department of
Radiology, Sibley Hospital, Washington, DC
n Abstract: Triple-negative (TN) breast cancers, which are associated with a more aggressive clinical course and poorer
prognosis, often present with benign imaging features on mammography and ultrasound. The purpose of this study was to
compare the magnetic resonance imaging features of TN breast cancers with estrogen (ER) and progesterone (PR) positive, human epidermal growth factor receptor (HER2) negative cancers. Retrospective review identified 140 patients with
TN breast cancer who underwent a preoperative breast MRI between 2003 and 2008. Comparison was made to 181
patients with ER+/PR+/HER2 cancer. Breast MRIs were independently reviewed by two radiologists blinded to the pathology. Discrepancies were resolved by a third radiologist. TN cancers presented with a larger tumor size (p = 0.002), higher
histologic grade (<0.001), and were more likely to be unifocal (p = 0.018) compared with ER+/PR+/HER2 tumors. MRI
features associated with TN tumors included mass enhancement (p = 0.026), areas of intratumoral high T2 signal intensity
(p < 0.001), lobulated shape (p < 0.001), rim enhancement (p < 0.001), and smooth margins (p = 0.005). Among the TN
tumors with marked necrosis, 26% showed a large central acellular zone of necrosis. n
Key Words: breast cancer, MRI, TN, triple negative
T
riple-negative (TN) breast cancers lack expression
of estrogen receptors, progesterone receptors, and
HER2. They account for ~12–26% of all breast cancers,
and are associated with a more aggressive clinical course
and poorer prognosis, including increased incidence of
local recurrence and metastatic disease, particularly to
the lung and brain (1–6). These cancers do not respond
to hormonal therapy or treatments targeting the HER2
receptor. Because of this, currently, no specific targeted
therapy is available for TN tumors; local treatment and
systemic chemotherapy is the primary treatment (3,7).
Approximately 70–85% of TN cancers have a clinical behavior similar to the basal-like subtype of
tumors (2,3,8–10). Both have a propensity to occur in
younger, usually premenopausal, women, and are
more common in African-American women, accounting for 20–27% of breast cancers in this group
(2,5,6,11). TN and basal-like cancers also account for
Address for correspondence and reprint requests to: Janice Sung, MD,
Memorial Sloan-Kettering Cancer Center, 300 East 66th Street, New York,
NY 10065, USA, or e-mail: [email protected]
DOI: 10.1111/tbj.12182
© 2013 Wiley Periodicals, Inc., 1075-122X/13
The Breast Journal, Volume 19 Number 6, 2013 643–649
more than 75% of tumors in women with the BRCA1 gene mutation (4,12,13).
Prior reports have described the imaging features of
TN breast cancers. These most commonly present
mammographically as a round, oval, or lobulated mass
without calcifications and are less likely to demonstrate
typical characteristics of malignancy, such as an irregular shape or spiculated margins (14–17). A similar
appearance has been described for breast cancers developing in patients with a BRCA-1 mutation. Sonographically, TN cancers are more likely to present as a mass
and to have circumscribed margins (15–17). The imaging features of TN tumors on MRI have also been
described in several studies. However, the number of
TN cancers evaluated in these studies was small,
between 29 and 59 tumors (16,18,19). The purpose of
our study was to evaluate the magnetic resonance (MR)
imaging features of TN breast cancers in comparison to
the more common ER+/PR+HER2 cancers in a larger
study population.
MATERIALS AND METHODS
Our institutional review board approved this HIPAA compliant study, and the need for informed
644 • sung et al.
consent was waived. Retrospective review of the
radiology department data base identified 140
patients with pathologically confirmed TN breast
cancer who underwent a preoperative breast MRI
between 2003 and 2008. Comparison was made to
181 randomly selected patients with ER+/PR+/
HER2 breast cancer who also had undergone a
preoperative breast MRI during the same period.
Pathology records were reviewed for age at diagnosis,
tumor size, histologic grade, lesion focality (unifocal
versus multifocal/multicentric), and axillary nodal
involvement.
Breast MRI was performed with the patient prone
in a 1.5- or 3-T commercially available system (Sigma,
General Electric Medical Systems, Milwaukee, WI)
using a dedicated surface breast coil. Imaging
sequences included a localizing sequence, a sagittal
fat-suppressed T2-weighted sequence, and T1weighted three-dimensional, fat-suppressed fast spoiled
gradient-echo sequences before and three times after
rapid bolus injection of 0.1 mmol/L of gadopentetate
dimeglumine (Magnevist, Berlex, Wayne, NJ) per kilogram of body weight. Table 1 outlines our standard
imaging protocol.
The preoperative MRIs for patients with TN and
ER+/PR+/HER2
were independently reviewed by
two dedicated breast imaging radiologists with 5 and
6 years of experience interpreting breast MRI who
were blinded to the histology. Discrepancies were
resolved by third radiologist with 9 years of experience who was also blinded to the pathology. Results
were reported using the Breast Imaging Reporting and
Data System (BI-RADS) lexicon (20). Lesions were
described as having either mass or nonmass enhancement. High intratumoral T2 signal intensity was
defined as signal equivalent to fluid in cysts or lymph
nodes. The shape, enhancement pattern, margins, and
enhancement kinetics were described for all mass
lesions.
Statistics
A total of 181 ER+/PR+/HER2 patients with preoperative breast MRI who underwent surgery in the
same time period as the TN cancer patients were randomly selected. Patient age and disease characteristics
were summarized by disease type. To test if the different
disease types had variate features, the Wilcoxon rank
sum test was used for continuous variables and the Fisher’s exact test was used for categorical variables.
Pathology
One breast pathologist (YW) retrospectively
reviewed the H & E-stained sections of the tumors,
and interpreted the histopathologic findings without
knowledge of the MR findings. Immunohistochemical
analyses for ER, PR, and HER2 were also verified by
the same breast pathologist, following the current
ASCO CAP guidelines. All TN breast carcinomas in
this study group were ER/PR negative (no nuclear
staining) and HER2 negative (0/1+).
RESULTS
Clinical Findings
The study population consisted of 140 patients
with TN breast cancer and 181 patients with ER+/
PR+/HER2 breast cancer (Table 2). There was no
statistical difference in patient age, with a median of
49 in both groups (p = 0.244). BRCA status was
available for 42 of TN patients and 48 of the ER+/
PR+/HER2 patients. Of these, 19/42 (86%) of the
TN patients had a BRCA-1 or -2 mutation, compared
to 3/48 (14%) of the ER+/PR+/HER2
patients
(p < 0.001). The TN tumors were larger in size at the
time of presentation, with a median of 1.7 cm (range:
0.2–9 cm), compared with a median size of 1.4 cm
Table 1. Standard MRI Imaging Protocols at 1.5 and 3T
Sequence
Scout
Sagittal T2 fat- saturated
Sagittal T1 nonfat-saturated
Sagittal T1 fat-saturated precontrast
Sagittal T1 fat-saturated postcontrast 9 3
Axial T1 fat-saturated postcontrast
TE (msec)
TR (msec)
Flip angle (°)
FOV (cm)
Slice thickness (mm)
Minimal
102
2.2
2.2
2.2
2.2
150
4000
70
90
10
10
10
10
48
18–22
18–22
18–22
18–22
28–36
10
3
3
3
3
1 at 1.5T
0.8 at 3T
Matrix
256
192
256
256
256
320
384
9
9
9
9
9
9
9
NEX
128
256
192
192
192
320 at 1.5 T
384 at 3T
1
2
1
1
1
1
MRI features of TN Breast Cancers • 645
Table 2. Clinical Characteristics of Patients with
TN and ER+/PR+/HER2 Breast Cancers
Characteristic
Age (years)
Tumors size (cm)
Histologic grade
Grade I
Grade II
Grade III
NA
Focality
Unifocal
Multifocal/multicentric
Axillary status
Positive
Negative
NA
TN (n = 140)
ER+/PR+/
HER2 (n = 181)
p-value
49 (29–72)
1.7 (0.2–9)
49 (31–74)
1.4 (0.1–11)
0.244
0.002
0
11 (8%)
124 (89%)
5 (4%)
23
62
67
29
(13%)
(34%)
(37%)
(16%)
<0.001
78 (56%)
62 (44%)
76 (42%)
105 (58%)
0.018
50 (36%)
85 (61%)
5 (4%)
68 (38%)
113 (62%)
0 (0%)
1.000
(a)
(b)
TN, triple-negative; ER, estrogen receptor; PR, progesterone receptor; HER, human
epidermal growth factor receptor.
(range: 01–11 cm) in the ER+/PR+/HER2 tumors
(p = 0.002). TN tumors were also associated with
a higher histologic grade. 124 (89%) of the TN
tumors were of a histologic grade 3, compared with 67
(37%) of the ER+/PR+/HER2 tumors (p < 0.001).
78 (56%) of the TN cancers presented as a unifocal
lesion and 62 (44%) with multifocal or multicentric disease, compared with 76 (42%) and 105
(58%) of the ER+/PR+/HER2 tumors, respectively
(p = 0.018). There was no significant difference in
axillary nodal involvement between the TN or ER+/
PR+/HER2 tumors (p = 1.000).
The majority of tumors in both groups were invasive ductal carcinomas (IDC). Of the 140 TN breast
cancer, 133 (95%) were IDC, and there were four
invasive mammary carcinomas, two invasive lobular
carcinomas, and one metaplastic carcinoma. Of the
ER+/PR+/HER2 tumors, 143 (79%) were IDC, and
there were 11 invasive mammary carcinomas and 27
invasive lobular carcinomas.
MRI Findings
Type of Lesion Enhancement One hundred and fifteen (82%) of the TN tumors presented with mass
enhancement, and 25 (18%) with nonmass enhancement, compared with 129 (71%) and 52 (29%) of the
ER+/PR+/HER2 tumors, respectively (p = 0.026).
T2 Intratumoral Signal Intensity The majority of
the mass lesions did not demonstrate areas of high T2
intratumoral signal intensity in either group. When
present, high intratumoral T2 signal intensity was sig-
Figure 1. Example of a triple-negative breast cancer in a 63-yearold woman. (a) Sagittal fat-suppressed T2-weighted MR image
shows a mass with high intratumoral signal intensity. (b) Sagittal
fat-suppressed postcontrast T1-weighted images demonstrate a
mass with a round shape, smooth margins, and rim enhancement.
nificantly associated with TN tumors, evident in
29 (25%) of TN tumors, compared with only 10
(8%) of the ER+/PR+/HER2
tumors (p ≤ 0.001;
Figs. 1 and 2).
Features of Mass Enhancement The distribution of
mass shape was significantly different between TN
and ER+/PR+/HER2 tumors (p < 0.001), with TN
tumors presenting most often with a lobulated shape
(70/115, 61%) compared with the ER+/PR+/HER2
tumors, which were more likely to present as an irregular mass (66/129, 51%; Fig. 2 and Table 3). 57%
(65/115) of the TN tumors demonstrated rim enhancement, while 78% (100/129) of the ER+/PR+/HER2
tumors presented as a heterogeneously enhancing mass
(p < 0.001). Although most masses in both groups
had irregular margins, smooth margins, when present,
646 • sung et al.
(a)
Table 3. MR Imaging Features of TN and ER+/
PR+/HER2
Tumors Presenting with Mass
Enhancement
MR imaging finding
(b)
Intratumoral T2 SI
High
Intermediate/low
Mass shape
Round/oval
Lobulated
Irregular
Internal enhancement
Homogeneous
Heterogeneous
Rim
Mass margins
Smooth
Irregular
Kinetics
Persistent/plateau
Washout
TN (n = 115)
ER+/PR+/HER2
(n = 129)
p-value
29 (25%)
86 (75%)
10 (8%)
119 (92%)
<0.001
16 (14%)
70 (61%)
29 (25%)
16 (12%)
47 (36%)
66 (51%)
<0.001
2 (1%)
48 (42%)
65 (57%)
6 (5%)
100 (78%)
23 (18%)
<0.001
30 (26%)
85 (74%)
15 (12%)
114 (88%)
0.005
46 (40%)
69 (60%)
56 (43%)
73 (57%)
0.605
Figure 2. Example of a triple-negative breast cancer in a 36-yearold woman. (a) Sagittal fat-suppressed T2-weighted MR image
shows a mass with high intratumoral signal intensity. (b) Sagittal
fat-suppressed postcontrast T1-weighted images demonstrate a
mass with a lobulated shape, irregular margins, and rim enhancement.
were seen significantly more frequently with TN (30/
115, 26%) than ER+/PR+/HER2 tumors (15/129,
12%, p = 0.005; Fig. 1). The majority of lesions in
both groups demonstrated washout kinetics (69/115,
60% for TN, 73/129, 57% for ER+/PR+/HER2 ;
p = 0.605).
Pathology Pathology slides were available for 22
TN tumors with high intratumoral T2 signal intensity;
slides for seven patients were not available for review.
The median tumor size was 2.1 cm (range 0.9–5 cm).
The histologic subtypes were ductal carcinoma, NOS
(n = 14), metaplastic carcinoma (n = 2), ductal carcinoma with focal matrix production (n = 3), apocrine
carcinoma (n = 2), and ductal carcinoma with neuroendocrine differentiation and focal small cell features
Figure 3. A representative tumor with large central acellular zone
(LCAZ) of necrosis. (H & E stain, 49).
(n = 1). Necrosis was observed in 18 (82%) of 22
tumors, of which, 9 (41%) had marked necrosis
(>50% of the tumor), five (23%) had moderate necrosis (5–50% of the tumor), and four (18%) had minimal or focal necrosis (<5% of the tumor). Among the
tumors with marked necrosis, six (27%) showed the
morphological features of central necrosis and fibrosis
(CNF), also known as large central acellular zone
(LCAZ) of necrosis (Fig. 3). The remaining three
tumors with marked necrosis other than LCAZ had
geographic necrosis (Fig. 4).
MRI features of TN Breast Cancers • 647
DISCUSSION
Breast cancer is a diverse disease, encompassing
tumors with a wide spectrum of clinical, pathologic,
molecular, and imaging characteristics. In addition to
tumor size, histologic grade, and lymph node status,
the expression of hormonal and HER2 receptors has
important prognostic implications and contributes to
selection of optimal treatment strategies. Therefore,
determination of marker status has become standard
practice prior to treatment planning (10). Microarraybased expression profiling studies have identified five
subgroups of breast cancers, including luminal A,
luminal B, basal- like, HER2 enriched, and normal
Figure 4. A representative tumor with geographic necrosis (H & E
stain, 409).
breast-like tumors (21). Basal-like breast cancers are
among the most aggressive of these subtypes (21–24).
Although not synonymous, the majority of basal-like
cancers are also TN breast cancers and the majority
of TN breast cancers are also basal-like cancers,
which are said to exhibit BRCA-like behavior (2,3,8).
The TN subgroup is characterized by the absence or
low levels of expression of ER, PR, and HER2 expression and expression of genes usually found in the
basal or myoepithelial cells of the breast (7,22).
Several published reports have evaluated the MR
imaging appearance of TN tumors. However, the
number of TN cancers evaluated in these studies was
small, including between 29 and 59 cancers
(16,18,19). Our study is the largest study performed
to date, including 140 TN cancers. The Uematsu
study, which included 59 TN breast cancers, and the
Dogan study, which included 44 patients with TN
tumors, reported unifocal disease in 66% and 77%,
respectively (16,18). In our study, TN tumors were
also more likely to be unifocal disease, although to a
lesser extent, with 56% of 140 TN tumors demonstrating unifocality.
Prior studies have reported that 77–97% of TN
tumors presented with mass enhancement (16,18,19).
Our study confirmed this strong association between
TN tumors and mass enhancement, with 82% of TN
cancers presenting as an enhancing mass.
The majority of TN tumors did not contain areas
of high T2 intratumoral signal intensity. However,
when present, this feature was associated with TN
Table 4. Comparison of MR Imaging Features of TN Tumors Presenting with Mass Enhancement in
Published Reports
Characteristic
Intratumoral T2 SI
High
Intermediate/low
Shape
Round/oval
Lobulated
Irregular
Lesion enhancement
Homogeneous
Heterogeneous
Rim
Margins
Smooth
Irregular
Kinetics
Washout
Persistent/plateau
MSKCC (n = 115)
Chen (n = 29)
Uematsu (n = 56)
Dogan (n = 34)
25%
75%
NA
NA
46%
54%
48%
52%
14%
61%
25%
NA
NA
NA
41%
41%
18%
47%
41%
12%
1%
42%
57%
(59%)*
(59%)*
41%
0%
20%
8%
6%
18%
77%
26%
74%
NA
NA
39%
61%
12%
88%
60%
40%
100%
0%
50%
50%
91%
9%
*In this study, lesion enhancement was separated into those with and without rim enhancement only.
648 • sung et al.
tumors. This imaging finding was less frequent in our
study (25%) compared with prior published reports
(46–48%; Table 4) (16,18). The reason for this variability remains unclear. One potential explanation
may relate to differences in lesion size. The mean size
of TN tumors in our study was 2.2 cm, compared
with 3.7 in the Dogan study, although the mean TN
tumor size in the Uematsu study was 2.1 cm.
57% of the TN masses demonstrated rim enhancement. Rim enhancement has a high predictive value
for malignancy, but is an infrequent imaging appearance of breast cancers (25,26). The frequency of TN
tumors demonstrating rim enhancement in the literature has ranged between 41% and 80% (16,18,19).
61% of the TN tumors presenting with mass
enhancement had a lobulated shape, and 14% with a
round/oval shape. TN tumors have been reported to
present mammographically most commonly as a
round, oval, or lobulated mass (14–17). An irregular
shape, which was the most common shape of the
ER+/PR+/HER2 tumors, was infrequently seen with
TN tumors, present in 25%. Prior series have
described that TN tumors are having an irregular
shape on MRI in only 12–18% of tumors (16,18).
Although the majority of the TN tumors, like other
subtypes of breast cancer, have irregular margins,
smooth margins, when present, were seen significantly
more often in TN tumors than in ER+/PR+HER2
tumors, present in 26%, compared with between 12%
and 39% of TN tumors in prior reports (16,18).
Appreciating the imaging features of TN cancers is
important, especially as some individual features, such
as round shape, smooth margins, and internal areas of
high T2 signal intensity, are frequently associated with
benign etiologies. This appearance may actually reflect
the aggressive nature of TN tumors as high-grade
tumors are more likely to present as a well-defined mass,
while lower grade tumors are more likely to cause a desmoplastic reaction in the adjacent breast tissue resulting
in an irregular margin (27,28). This appearance also correlates with our knowledge of the appearance of tumors
in patients carrying the BRCA-1 mutation. Interestingly,
23–38% of familial breast cancers demonstrate benign
morphologic features, including an oval or round shape
and smooth margins (27,29). However, the internal
enhancement characteristics of TN tumors, which
almost all demonstrated either heterogeneous or rim
enhancement, are suggestive of malignancy.
Even within the TN group, there is biologic heterogeneity. Marked necrosis was present on pathology in
9/22 TN tumors with high T2 signal intensity. Among
these, six (27%) showed the morphological features of
CNF, also known as LCAZ of necrosis (28,30) (Fig. 3),
a morphological feature that has been shown to be
associated with higher risks of lung and brain metastases, poor outcome and disease-free survival (30,31).
The remaining three tumors with marked necrosis other
than LCAZ had geographic necrosis (Fig. 4), a frequent
finding in basal-like breast cancer (32).
The relationship between tumor size and axillary
nodal status is not straightforward with TN tumors.
Axillary nodal involvement was similar between TN
and ER+/PR+/HER2 patients in our study. Prior
studies have reported conflicting results regarding the
prevalence of lymph node metastases in TN and basallike tumors. One large series found that basal-like
cancers were more likely than other subtypes to be
node-negative, while other studies have reported higher
or no differences in rates of node positivity (4,33,34).
Hernandez-Aya et al. have recently reported that the
number of positive nodes in their TN patients was not
predictive of outcome and in fact the only significant
difference in prognosis was in the N0 group (35).
Limitations of this study include that this was a retrospective study. The number of patients, while larger
than prior published reports, is still relatively small. In
addition, comparison was made to only ER+/PR+/
HER2 tumors.
In conclusion, our study demonstrates that certain
imaging features are more frequent with TN tumors
compared with ER+/PR+HER2
tumors. Better
understanding of the imaging features of TN cancers
provides an imaging biomarker with clinical implications.
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