AJCP / ORIGINAL ARTICLE
A Clinicopathologic Analysis of 45 Patients With
Metaplastic Breast Carcinoma
Ashley Cimino-Mathews, MD,1,2 Sangita Verma, MD,3*
Maria Cristina Figueroa-Magalhaes, MD,2* Stacie C. Jeter, CCRP,2 Zhe Zhang, MS,2
Pedram Argani, MD,1,2 Vered Stearns, MD,2 and Roisin M. Connolly, MBBCh2
From the 1Department of Pathology, Johns Hopkins Hospital, Baltimore, MD; 2Department of Oncology, Sidney Kimmel Comprehensive Cancer Center,
Johns Hopkins School of Medicine, Baltimore, MD; and 3Department of Internal Medicine, St Agnes Hospital, Baltimore, MD.
Key Words: Metaplastic breast carcinoma; Sarcomatoid breast carcinoma
Am J Clin Pathol March 2016;145:365-372
DOI: 10.1093/AJCP/AQV097
ABSTRACT
Objectives: Metaplastic breast carcinomas (MBCs) are
rare, aggressive cancers lacking targeted therapy. Here, we
review the clinicopathologic features, treatment, and out-
comes of patients with MBC treated at our institution.
Methods: We searched clinical and pathology databases for
patients with histologically confirmed MBC from 1999 to
2012. We estimated survival probabilities using the Kaplan-
Meier method and evaluated prognostic factors using Cox
regression.
Results: Forty-five cases were identified, including chon-
droid (24%), spindled (20%), sarcomatoid (16%), squamous
(11%), and mixed (29%) histologic subtypes. Median tumor
size was 3 cm, with 86% grade III and 69% triple-negative
for estrogen receptor, progesterone receptor, and human
epidermal growth factor receptor 2. Most had negative
lymph nodes, and two patients had metastases at diagnosis.
Six patients received neoadjuvant therapy, with one patho-
logic complete response. All patients underwent surgery,
60% received adjuvant radiation, and 58% had adjuvant
chemotherapy. Five-year recurrence-free survival was
64%; 5-year overall survival was 69%. Tumor size, history
of breast cancer, and mixed histology were associated with
inferior outcomes.
Conclusions: We report one of the largest single-institution
series of patients with MBC. MBC is associated with a poor
prognosis, despite low nodal involvement. Most patients in
this series had high-grade, triple-negative tumors and were
treated with optimal therapy.
© American Society for Clinical Pathology, 2016. All rights reserved.
For permissions, please e-mail: journals.permissions@oup.com
365
Invasive breast carcinoma is the second leading cause of
cancer mortality in women in the United States.1 Metaplastic
breast carcinomas (MBCs) comprise a rare but aggressive
subtype and represent less than 5% of invasive breast carcin-
omas.2 Histologically, MBC is characterized by the presence
of divergent cellular differentiation and heterologous elem-
ents, including squamous, spindled, sarcomatoid/pleo-
morphic, chondroid, and osseous differentiation.2-8 MBC
may arise with or without an associated conventional inva-
sive ductal carcinoma (IDC) component, and some degree of
clonality has been demonstrated between these components
in the few studies examining this area.9,10
Most MBCs do not express the estrogen receptor (ER),
progesterone receptor (PR), or human epidermal growth fac-
tor receptor 2 (HER2) (ie, “triple negative”).2 Compared
with patients with conventional IDC, those diagnosed with
MBC are less likely to have axillary lymph node involve-
ment, yet are more likely to have metastatic disease at first
presentation.11-17 In addition, patients with MBC have a
lower rate of pathologic complete response to neoadjuvant
chemotherapy18 and experience worse overall survival
(OS).11,16,17,19-22
Evidence as to how to manage patients with MBC is
derived largely from a number of single-institution case ser-
ies and usually follows the treatment paradigm for conven-
tional IDC. However, the 5-year survival rate for this rare
breast cancer subtype is approximately 65% compared with
89% for conventional IDC, despite aggressive standard local
and systemic treatment. Due to the rarity of the condition,
only a few case reports23,24 and phase I clinical trials25 have
reported clinical activity of investigational treatment strat-
egies in patients with MBC. Further study is clearly required
Am J Clin Pathol 2016;145:365-372 365
DOI: 10.1093/ajcp/aqv097
Cimino-Mathews et al / METAPLASTIC BREAST CARCINOMA
to optimize outcomes for patients with this rare breast can-
cer subtype. We reviewed the clinicopathologic features,
treatment strategies, and clinical outcomes of patients with
MBC treated at the Johns Hopkins Hospital over a 13-year
period to further define the behavior of these neoplasms and
to identify potential prognostic biomarkers.
Materials and Methods
Data Collection
This study was approved by the Institutional Review
Board of the Johns Hopkins University (JHU). Both a clin-
ical database (the JHU Integrated Breast Cancer Research
Database) and the pathology archives were searched over
a 13-year period (1999-2012) for adult women older than
18 years with a histologically confirmed diagnosis of meta-
plastic or sarcomatoid breast carcinoma who received treat-
ment at our institution. Pathology database search terms
included breast carcinoma AND metaplastic OR sarcomatoid.
All diagnoses were confirmed by institutional pathologists be-
fore the initiation of clinical treatment. Cases without a defini-
tive pathologic diagnosis of MBC (eg, “malignant tumor favor
metaplastic carcinoma”) were excluded. Data were entered
into an electronic research database and reviewed for com-
pleteness and accuracy. Data points included clinicopathologic
features (ie, patient age, patient race, tumor type, tumor stage,
tumor grade, tumor size, ER/PR/HER2 status of tumor, Ki-67
proliferation index when available, pathologic response [if
neoadjuvant therapy was administered]), as well as local and
systemic treatments received, the development of disease re-
currences, and survival. ER and PR positivity were defined as
any nuclear labeling 1% or higher. HER2 positivity was
defined as an immunohistochemistry score of 3þ or fluores-
cence in situ hybridization ratio of 2.2 or more.
Statistical Analysis
Demographics and clinicopathologic features were
summarized by use of descriptive statistics. The clinical out-
comes examined in this retrospective analysis included OS,
recurrence-free survival (RFS), and distant metastasis–free
survival (DMFS). OS was calculated as the time from diag-
nosis to death due to any cause, with patients who were alive
censored at the time of last follow-up. RFS was calculated
as the time from surgery to the time of first documentation
of breast cancer recurrence at any site (ie, in-breast, axillary,
chest wall, or distant metastases) or deaths due to breast can-
cer, whichever occurred first. Patients who did not have re-
currence of disease but died of other unrelated causes were
censored at the time of death. DMFS was calculated as the
time from surgery to the time of first documentation of
366 Am J Clin Pathol 2016;145:365-372
366 DOI: 10.1093/ajcp/aqv097
distant metastasis. Local or regional recurrence without dis-
tant metastasis was censored at the time of recurrence. Two
patients who had metastatic disease at diagnosis were
included in the calculations as failures, with both RFS and
DMFS of zero. Survival probabilities at 5 years were esti-
mated using the Kaplan-Meier method, and 95% confidence
intervals (CIs) were obtained using the Greenwood formula.
The distributions of clinical outcomes (ie, OS, RFS, and
DMFS) were compared using the log-rank test. Univariate
Cox regression analysis was performed to evaluate the prog-
nostic impact of various clinicopathologic factors on OS,
RFS, and DMFS. The hazard ratios (HRs) were estimated
with 95% CIs. Multivariate analysis was not performed due to
the limited sample size and small number of events. All statis-
tical tests were two-sided with significance level considered at
P < .05, and the analyses were carried out using the statistical
software SAS (version 9.3; SAS Institute, Cary, NC) and
R (version 2.15.2).
Results
Clinicopathologic Features
Forty-five female patients with a confirmed diagnosis
of metaplastic or sarcomatoid carcinoma were identified.
The clinicopathologic features of these patients and their
tumors are detailed in Table 1 . The median patient age was
59 years (range, 38-93 years), and median tumor size at the
time of surgical resection was 3 cm (range, 1-14.8 cm).
Most patients (62%) had T2 disease (tumor size 2-5 cm),
and positive lymph node metastases were documented at
diagnosis in 24% of patients. Two (4.4%) patients had meta-
static disease at diagnosis, with metastases to the liver and
bone (n ¼ 1) and to the skin (n ¼ 1).
The histologic subtypes of the metaplastic components
varied from a single metaplastic component to mixed com-
ponents, consisting of any degree of squamous, chondroid,
spindled, and pleomorphic/sarcomatoid elements Image 1 .
The histologic subtypes identified were chondroid (24%),
spindled (20%), sarcomatoid/pleomorphic (16%), squamous
(11%), and mixed/other (29%). Most patients (73%) had an
associated conventional IDC component in association with
the metaplastic or sarcomatoid component. Of these, all
were invasive carcinomas of no special type (invasive ductal
carcinoma or invasive mammary carcinoma with ductal and
lobular features), and none were invasive lobular carcin-
omas or other special-type carcinomas. Most tumors (69%)
were triple negative, 20% were ER/PR positive, and 9%
were HER2 positive. Histologic tumor grade was docu-
mented in 44 cases; of these, 86% were Elston grade III, and
14% were Elston grade II.
© American Society for Clinical Pathology
 AJCP / ORIGINAL ARTICLE

Table 1 Table 1 (cont)

Clinicopathologic Characteristics of 45 Patients With
Clinicopathologic Parameter Number (%)
Metaplastic Breast Carcinomaa
Adjuvant chemotherapy for MBC
Clinicopathologic Parameter Number (%)
No 19 (42)
Age at diagnosis, median (range), y 59 (38-93) Yes 26 (58)
Race Chemotherapy for previous cancer 3 (10)
White 28 (62) Adjuvant trastuzumab for MBC
Black 16 (36) No 44 (98)
Other 1 (2) Yes 1 (2)
History of breast cancer Adjuvant hormone therapy for MBC
Yes 8 (18) No 40 (89)
No 37 (82) Yes 5 (11)
Tumor size, cm Hormonal therapy for previous cancer 2 (28)
<2 9 (20)
ER, estrogen receptor; HER2, human epidermal growth factor receptor 2; IDC, con-
2-5 28 (62) ventional invasive ductal carcinoma; MBC, metaplastic breast carcinoma; pCR, com-
>5 8 (18) plete pathologic response; PR, progesterone receptor.
Nodal status a
Values are presented as number (%) unless otherwise indicated.
Positive 11 (24)
Negative 23 (51)
Unknown 11 (24)
Metastasis (stage IV) at diagnosis
No 43 (96) Treatment Characteristics
Yes 2 (4) Neoadjuvant therapy (anthracycline-taxane based in
Histologic subtype
83%) was administered in 13% of patients (n ¼ 6), with one
Squamous 5 (11)
Sarcomatoid 7 (16) patient achieving complete pathologic response to dose-
Spindle 9 (20) dense doxorubicin and cyclophosphamide followed by
Chondroid 11 (24) weekly paclitaxel. All patients underwent lumpectomy
Mixed-other 13 (28)
Associated IDC at diagnosis (53%) or mastectomy (47%), with 91% undergoing axillary
No 12 (27) nodal sampling. Four (9%) patients had positive final mar-
Yes 33 (73) gins (defined as tumor present at or < 1 mm from the inked
Hormone receptors
ER and/or PR positive 9 (20)
final resection margin), but two of these patients also had
ER and PR negative 36 (80) metastatic disease at presentation. Three of these patients
HER2 died due to disease shortly after diagnosis, and the third had
Positive 4 (9)
no evidence of local recurrence at last follow-up.
Negative 38 (84)
Unknown 3 (7) Adjuvant radiation therapy was administered for
Triple negative (ER–/PR–/HER2–) 31 (69) the metaplastic carcinoma in 60% of patients, adjuvant
Tumor grade chemotherapy in 58%, hormonal therapy in 11%, and
Elston grade I 0 (0)
Elston grade II 6 (14) trastuzumab in 2%. Of those who received adjuvant chemo-
Elston grade III 38 (86) therapy (n ¼ 26), the regimens were primarily anthracycline
Unknown 2 and taxane based—specifically, anthracycline and taxane
Ki-67
<30% 7 (16)
based (n ¼ 12), anthracycline based (n ¼ 2), taxane based
30% 19 (42) (n ¼ 3), anthracycline and taxane with trastuzumab (n ¼ 1),
Unknown 19 (42) and cyclophosphamide, methotrexate, and 5-fluorouracil
Neoadjuvant chemotherapy for MBC
(n ¼ 1). Only one of four patients with HER2-positive dis-
No 39 (87)
Yes 6 (13) ease received adjuvant trastuzumab; two patients were diag-
pCR nosed before the availability of trastuzumab, and another
Yes 1 (17) declined HER2 targeted treatment.
No 5 (83)
Local regional therapy for MBC
Lumpectomy with nodal sampling 21 (47)
Lumpectomy without nodal sampling 3 (7) Survival Analysis
Mastectomy with nodal sampling 20 (44)
Mastectomy without nodal sampling 1 (2) Five-year OS was 69% (95% CI, 45%-93%) at a me-
Adjuvant radiation therapy for MBC dian follow-up of 28 months (range, 2-138 months) Figure
No 18 (40) 1A , 5-year RFS was 64% (95% CI, 39-89%) at a median
Yes 27 (60)
Radiation for previous cancer 4 (12)
follow-up of 26 months (range, 2-137 months) Figure 1B ,
and 5-year DMFS was 75% (95% CI, 50%-99%)
Figure 1C . Univariate Cox regression analyses for

© American Society for Clinical Pathology Am J Clin Pathol 2016;145:365-372 367

367 DOI: 10.1093/ajcp/aqv097
Cimino-Mathews et al / METAPLASTIC BREAST CARCINOMA

Image 1 Histologic appearances of metaplastic breast carcinoma. Metaplastic breast carcinomas are defined by the presence
of any degree of heterologous elements such as squamous (A), chondroid (B), spindled (C), and/or pleomorphic/sarcomatoid
(D), with or without an accompanying conventional in situ or invasive mammary carcinoma component (H&E, 20).

associations between clinicopathologic features and OS,
RFS, and DMFS, as well as the HR and 95% CI, are pre-
sented in Table 2 . Univariate analysis indicated that tumor
size more than 5 cm (HR, 6.2; 95% CI, 1.1-35.7; P ¼ .039),
positive final surgical margins (HR, 5.4; 95% CI, 1.4-20.5;
P ¼ .014), personal history of breast cancer (HR, 5.0; 95%
CI, 1.5-16.6; P ¼ .008), and no adjuvant chemotherapy
(HR, 3.67; 95% CI, 1.1-12.4; P ¼ .036) were all associated
with worse OS (Table 2 and Figure 1D ). Positive final sur-
gical margins (HR, 7.7; 95% CI, 2.0-30.2; P ¼ .004) and per-
sonal history of breast cancer (HR, 6.2; 95% CI, 1.9-19.7;
P ¼ .002) were also associated with worse RFS (Table 2
and Figure 1E ). Finally, positive surgical margins (HR,
9.0; 95% CI, 2.2-36.8; P ¼ .002), personal history of breast
cancer (HR, 5.4; 95% CI, 1.4-21.0; P ¼ .014), and mixed
metaplastic histology (HR, 4.2; 95% CI, 1.1-15.7; P ¼ .032)
were all associated with worse DMFS (Table 2 and Figure
1F ). We did not observe a statistically significant associ-
ation between nodal status, hormone receptor status, Ki-67
proliferation index, adjuvant chemotherapy, or the concomi-
tant presence of a conventional in situ or IDC component
with survival outcomes. Multivariate analysis could not be
performed due to the limited sample size and small number
of events. The univariate association of surgical margin sta-
tus and worse outcome should thus be interpreted with cau-
tion, due to the low number of positive events as well as the
confounding factor that half of these patients also had a
higher stage of disease.

368 Am J Clin Pathol 2016;145:365-372 © American Society for Clinical Pathology

368 DOI: 10.1093/ajcp/aqv097
 AJCP / ORIGINAL ARTICLE

A Overall Survival (Fraction) 1.0 B 1.0

0.8 0.8

Survival (Fraction)
Recurrence-Free
0.6 0.6

0.4 0.4

0.2 0.2

0.0 0.0
0 2 4 6 8 10 12 0 2 4 6 8 10 12
Years After Diagnosis Years After Diagnosis

C 1.0 D 1.0

Overall Survival (Fraction)

Distant Metastasis-Free

0.8 0.8
Survival (Fraction)

0.6 0.6

0.4 0.4

0.2 0.2 No prior history of bca

(n = 37)
Prior history of bca
(n = 8)
0.0 0.0
0 2 4 6 8 10 12 0 2 4 6 8 10 12
Years After Diagnosis Years After Diagnosis

E 1.0 F 1.0
Distant Metastasis-Free

0.8 0.8
Survival (Fraction)
Survival (Fraction)
Recurrence-Free

0.6 0.6

0.4 0.4

0.2 No prior history of bca 0.2 No prior history of bca

(n = 37) (n = 37)
Prior history of bca Prior history of bca
(n = 8) (n = 8)
0.0 0.0
0 2 4 6 8 10 12 0 2 4 6 8 10 12
Years After Diagnosis Years After Diagnosis

Figure 1 Overall survival (OS) (solid line) with 95% confidence intervals (dashed lines) (A). Recurrence-free survival (RFS)
(solid line) with 95% confidence intervals (dashed lines) (B). Distant metastasis-free survival (DMFS) (solid line) with 95% confi-
dence intervals (dashed lines) (C). OS stratified by history of breast cancer (bca) (P ¼ .008) (D). RFS stratified by history of bca
(P ¼ .002) (E). DMFS by history of bca (P ¼ .014) (F). P values were obtained from log rank test.

Discussion
MBC is a subtype of invasive breast carcinoma patho-
logically defined by the presence of heterologous and diver-
gent differentiation, including any combination of
chondroid, osseous, pleomorphic/sarcomatoid, spindled, or
squamous components.2-8 MBCs may arise with or without
an accompanying conventional in situ or invasive mammary
carcinoma, and limited studies demonstrate clonality be-
tween these components in most cases investigated.9,10
Most MBCs are triple negative.2 Immunohistochemical and

© American Society for Clinical Pathology Am J Clin Pathol 2016;145:365-372 369

369 DOI: 10.1093/ajcp/aqv097
Cimino-Mathews et al / METAPLASTIC BREAST CARCINOMA

Table 2
Univariate Cox Regression Analysis for Association of Clinicopathologic Factors With Clinical Outcomes in 45 Patients With
Metaplastic Breast Carcinoma
Overall Survival Recurrence-Free Survival Disease Metastasis–Free Survival
Variable HR (95% CI) P Value HR (95% CI) P Value HR (95% CI) P Value
Age at diagnosis 1.01 (0.96-1.06) .738 1.01 (0.97-1.05) .726 1.01 (0.97-1.06) .600
Tumor size, cm
2-5 vs <2 1.08 (0.20-5.73) .926 0.42 (0.11-1.57) .198 0.50 (0.08-2.98) .445
>5 vs <2 6.24 (1.09-35.7) .039 1.78 (0.44-7.18) .415 3.40 (0.62-18.7) .159
Histology subgroup
Mixed vs nonmixed 2.09 (0.61-7.15) .241 2.12 (0.69-6.50) .188 4.22 (1.13-15.7) .032
Surgical margins
Positive vs negative 5.38 (1.41-20.5) .014 7.68 (1.95-30.2) .004 9.02 (2.21-36.8) .002
Nodal status
Negative vs positive 1.40 (0.35-5.57) .637 1.50 (0.30-7.43) .622 1.00 (0.18-5.46) .998
Hormone receptor status
ER and PR negative vs ER and/or PR positive 1.89 (0.41-8.71) .416 4.73 (0.61-36.7) .138 2.92 (0.36-23.5) .313
Triple negative
Yes vs no 2.79 (0.59-13.1) .195 6.41 (0.82-50.1) .077 3.88 (0.48-31.7) .206
Ki-67
30% vs <30% 3.73 (0.46-30.2) .218 2.63 (0.32-21.4) .367 2.63 (0.32-21.4) .367
History of breast cancer
Yes vs no 5.02 (1.52-16.6) .008 6.16 (1.93-19.7) .002 5.44 (1.41-21.0) .014
Concurrent IDC component
Yes vs no 0.95 (0.26-3.53) .944 1.78 (0.39-8.04) .456 1.10 (0.23-5.32) .904
Concurrent DCIS component
Yes vs no 1.38 (0.44-4.38) .585 1.39 (0.45-4.25) .565 1.09 (0.27-4.38) .900
Adjuvant chemotherapy for MBC
No vs yes 3.67 (1.09-12.4) .036 2.73 (0.89-8.38) .079 3.37 (0.84-13.5) .087
Adjuvant radiation therapy for MBC
No vs yes 2.54 (0.80-8.05) .112 1.50 (0.50-4.46) .469 1.41 (0.38-5.27) .607
CI, confidence interval; DCIS, ductal carcinoma in situ; ER, estrogen receptor; HR, hazard ratio; IDC, invasive ductal carcinoma; MBC, metaplastic breast carcinoma;
PR, progesterone receptor.

genomic studies have further characterized MBCs as mem-
bers of either the basal-like molecular subtype26-29 or the
claudin-low molecular subtype,19,30,31 with features of an
epithelial-to-mesenchymal transition and stem cell–like
characteristics, including increased presence of CD44þ/
CD24– tumor stem cells. However, in contrast to nonmeta-
plastic claudin-low breast carcinomas, MBCs also show an
increased proportion of mutations in PIK3CA,19 suggesting
a particular role for the P13K/AKT pathway in MBCs com-
pared with other claudin-low type carcinomas and illustrat-
ing tumoral heterogeneity even within a given molecular
subtype.
Despite molecular classification of MBCs that is similar
to basal-like or claudin-low subtypes of IDC, patients with
MBC experience inferior breast cancer outcomes compared
with conventional IDC. The available data in the literature
are limited to retrospective studies incorporating fewer than
100 patients with MBC each. These consistently reveal that
patients with MBC have fewer lymph node metastases but
more distant metastases,11-17 have worse OS,11,16,17,19-22 and
have a poorer response to chemotherapy18,19 than patients
with conventional IDC. In particular, several case-control
studies have included comparisons with IDC treated at the
same institution and confirmed worse OS in MBC compared
with matched conventional IDC.16,17
The presence of certain metaplastic elements has been
associated with varying prognoses. The presence of high-
grade spindled or pleomorphic components, for example,
has been associated with aggressive behavior such as meta-
stases,32,33 whereas the low-grade, fibromatosis-like meta-
plastic carcinomas with bland spindled cells have a high
risk of local recurrence but minimal risk of metastatic
spread.34 Of note, there were no patients with this latter
histologic subtype in our series. However, there is currently
no widely accepted prognostic value to either metaplastic
subtype or histologic grading in MBC.2 In addition, it is not
always clear from other published series whether a conven-
tional IDC component is present in association with
the metaplastic component. Thus, additional information is
clearly needed to further understand the disease pathogen-
esis and therefore improve management strategies for pa-
tients with MBC.
We present the clinicopathologic features, treatment
strategies, and clinical outcomes of 45 patients with MBC

370 Am J Clin Pathol 2016;145:365-372 © American Society for Clinical Pathology

370 DOI: 10.1093/ajcp/aqv097

treated at the Johns Hopkins Hospital over a 13-year period.
Although the data are limited by the relatively small number
of patients, retrospective nature of the analysis, and lack of
a case-control cohort, this study represents one of the largest
single-institution case series in the literature of the clinico-
pathologic features associated with this rare tumor type.
Furthermore, our data are consistent with the findings of the
largest published series of patients from the MD Anderson
Cancer Center.18 The MD Anderson investigators reported
that most cases of MBC were triple negative and that tumor
size but not the use of adjuvant chemotherapy or radiation
therapy was associated with poor outcome, and 5-year OS
(stages I-III) was 64%. In our series, 24% of patients with
MBC had lymph node metastases, which is in keeping with
rates of 24% to 28% seen in other single-institution ser-
ies.17-19 In our series, tumor size more than 5 cm and history
of breast cancer were associated with worse outcomes.
Mixed metaplastic histology was associated with worse
DMFS (P < .05). However, the interpretation of our data is
limited by the small sample size and low number of events.
Of note, there were only four patients with positive surgical
margins in our series, and three of these died due to their
disease shortly after diagnosis. The impact of positive mar-
gin on survival could have been confounded by other risk
factors such as stage at presentation. A larger study is
required to assess the independent effect of each variable on
prognosis in a multivariate analysis.
Most patients with MBC have high-grade, triple-nega-
tive disease that behaves more aggressively than conven-
tional IDC. It is clear from our data and that from other
institutions that, despite aggressive local and systemic man-
agement strategies, patients with MBC have suboptimal
breast cancer outcomes. Molecular and genomic analyses
have suggested that MBCs are enriched in the epithelial-to-
mesenchymal transition and cancer stem cell characteris-
tics,19,30,31 and MBCs have been reported to exhibit high
levels of angiogenesis markers such as vascular endothelial
growth factor.35 In this light, a phase I study included 12 pa-
tients with MBC and reported a 42% response rate (includ-
ing two cases of complete response) with the combination
of bevacizumab, temsirolimus (mammalian target of
rapamycin inhibitor), and liposomal doxorubicin,25 which
are agents believed to target these stem cell and angiogenic
characteristics. These results suggest that further studies
with these agents are warranted in MBC. Ideally, such stud-
ies should be performed at a national or an international
level based on the rarity of this tumor type. Case reports
also suggest that the administration of therapies commonly
used in the management of sarcomas in MBCs with sarco-
matoid features may be of benefit.23,24 Furthermore, there is
now the ability to assay small amounts of tumor tissue for
many genes and gene products that may lead to the
© American Society for Clinical Pathology
371
AJCP / ORIGINAL ARTICLE
identification of new targets and treatments. Larger studies
incorporating tumor biopsy specimens are clearly required
in an effort to identify potential prognostic and predictive
biomarkers in this rare and aggressive subtype of breast car-
cinoma, with the ultimate goal of guiding clinical trials with
novel investigational agents in this area of unmet need.
Corresponding author: Roisin M. Connolly, MBBCh, Sidney
Kimmel Comprehensive Cancer Center, Johns Hopkins School of
Medicine, 1650 Orleans St, CRB 1, Room 153, Baltimore,
MD 21287-0013; rconnol2@jhmi.edu.
Acknowledgments: We thank Christopher Umbricht, MD, PhD,
for independent confirmation of cases of metaplastic breast cancer
using the JHU Integrated Breast Cancer Research Database.
Supported by the Charles Evans Foundation (A.C.-M.), QVC
and Fashion Footwear Association of New York (R.M.C.), and
Johns Hopkins in vivo Cellular and Molecular Imaging Center
(NCI P50CA103175; Z.Z.).
*Dr Verma is now at Wake Forest School of Medicine, Winston-
Salem, NC; Dr Figueroa-Magalhaes is now at the Cancer Institute
of the State of São Paulo, São Paulo, Brazil.
References
1. Siegel R, Miller KD, Jemal A. Cancer statistics, 2015. CA
Cancer J Clin. 2015;65:5-29.
2. Reis-Filho JS, Lakhani SR, Gobbi H, et al. Metaplastic car-
cinoma. In: Lakhani SR, Ellis IO, Schnitt SJ, Tan PH, van de
Vijver MJ, eds. World Health Organization Classification of
Tumours of the Breast. Lyon, France: IARC; 2012:48-52.
3. Wargotz ES, Norris HJ. Metaplastic carcinomas of the breast,
I: matrix-producing carcinoma. Hum Pathol. 1989;20:628-
635.
4. Wargotz ES, Norris HJ. Metaplastic carcinomas of the breast,
II: spindle cell carcinoma. Hum Pathol. 1989;20:732-740.
5. Wargotz ES, Norris HJ. Metaplastic carcinomas of the breast,
III: carcinosarcoma. Cancer. 1989;64:1490-1499.
6. Wargotz ES, Norris HJ. Metaplastic carcinomas of the breast,
IV: squamous cell carcinoma of ductal origin. Cancer.
1990;65:272-276.
7. Wargotz ES, Norris HJ. Metaplastic carcinomas of the breast,
V: metaplastic carcinoma with osteoclastic giant cells. Hum
Pathol. 1990;21:1142-1150.
8. Rosen PP. Carcinomas with metaplasia. In: Rosen PP, ed.
Rosen’s Breast Pathology. 3rd ed. Philadelphia, PA: Lippincott
Williams & Wilkins; 2009:470-505.
9. Lien HC, Lin CW, Mao TL, et al. p53 overexpression and
mutation in metaplastic carcinoma of the breast: genetic evi-
dence for a monoclonal origin of both the carcinomatous and
the heterogeneous sarcomatous components. J Pathol.
2004;204:131-139.
10. Geyer FC, Weigelt B, Natrajan R, et al. Molecular ana-
lysis reveals a genetic basis for the phenotypic diversity
of metaplastic breast carcinomas. J Pathol. 2010;220:
562-573.
11. Rayson D, Adjei AA, Suman VJ, et al. Metaplastic breast
cancer: prognosis and response to systemic therapy. Ann
Oncol. 1999;10:413-419.
Am J Clin Pathol 2016;145:365-372 371
DOI: 10.1093/ajcp/aqv097
Cimino-Mathews et al / METAPLASTIC BREAST CARCINOMA
12. Al Sayed AD, El Weshi AN, Tulbah AM, et al. Metaplastic
carcinoma of the breast clinical presentation, treatment re-
sults and prognostic factors. Acta Oncol. 2006;45:188-195.
13. Park HS, Park S, Kim JH, et al. Clinicopathologic features
and outcomes of metaplastic breast carcinoma: comparison
with invasive ductal carcinoma of the breast. Yonsei Med J.
2010;51:864-869.
14. Bae SY, Lee SK, Koo MY, et al. The prognoses of metaplastic
breast cancer patients compared to those of triple-negative
breast cancer patients. Breast Cancer Res Treat.
2011;126:471-478.
15. Lee H, Jung SY, Ro JY, et al. Metaplastic breast cancer: clini-
copathological features and its prognosis. J Clin Pathol.
2012;65:441–416.
16. Lai HW, Tseng LM, Chang TW, et al. The prognostic sig-
nificance of metaplastic carcinoma of the breast (MCB)—a
case controlled comparison study with infiltrating ductal car-
cinoma. Breast. 2013;22:968-973.
17. Song Y, Liu X, Zhang G, et al. Unique clinicopathological
features of metaplastic breast carcinoma compared with inva-
sive ductal carcinoma and poor prognostic indicators. World
J Surg Oncol. 2013;11:129.
18. Hennessy BT, Giordano S, Broglio K, et al. Biphasic meta-
plastic sarcomatoid carcinoma of the breast. Ann Oncol.
2006;17:605-613.
19. Hennessy BT, Gonzalez-Angulo AM, Stemke-Hale K, et al.
Characterization of a naturally occurring breast cancer subset
enriched in epithelial-to-mesenchymal transition and stem
cell characteristics. Cancer Res. 2009;69:4116-4124.
20. Luini A, Aguilar M, Gatti G, et al. Metaplastic carcinoma of
the breast, an unusual disease with worse prognosis: the ex-
perience of the European Institute of Oncology and review of
the literature. Breast Cancer Res Treat. 2007;101:349-353.
21. Jung SY, Kim HY, Nam BH, et al. Worse prognosis of meta-
plastic breast cancer patients than other patients with triple-
negative breast cancer. Breast Cancer Res Treat.
2010;120:627-637.
22. Montagna E, Maisonneuve P, Rotmensz N, et al.
Heterogeneity of triple negative breast cancer: histologic
subtyping to inform the outcome. Clin Breast Cancer.
2013;13:31-39.
23. Brown-Glaberman U, Graham A, Stopeck A. A case of
metaplastic carcinoma of the breast responsive to chemo-
therapy with ifosfamide and etoposide: improved antitumor
response by targeting sarcomatous features. Breast J.
2010;16:663-665.
372 Am J Clin Pathol 2016;145:365-372
372 DOI: 10.1093/ajcp/aqv097
24. Chien T, Chou J, Chang T, et al. Successful treatment of bi-
phasic metaplastic sarcomatoid carcinoma of the breast by
evaluation of immunohistochemical markers. Hematol Oncol
Stem Cell Ther. 2010;3:89-93.
25. Moroney J, Fu S, Moulder S, et al. Phase I study of the anti-
angiogenic antibody bevacizumab and the mTOR/hypoxia-
inducible factor inhibitor temsirolimus combined with lipo-
somal doxorubicin: tolerance and biological activity. Clin
Cancer Res. 2012;18:5796-5805.
26. Reis-Filho JS, Milanezi F, Steele D, et al. Metaplastic breast
carcinomas are basal-like tumours. Histopathology.
2006;49:10-21.
27. Weigelt B, Horlings HM, Kreike B, et al. Refinement of
breast cancer classification by molecular characterization of
histological special types. J Pathol. 2008;216:141-150.
28. Weigelt B, Kreike B, Reis-Filho JS. Metaplastic breast car-
cinomas are basal-like breast cancers: a genomic profiling
analysis. Breast Cancer Res Treat. 2009;117:273-280.
29. Cimino-Mathews A, Subhawong AP, Elwood H, et al.
Neural crest transcription factor Sox10 is preferentially ex-
pressed in triple negative and metaplastic breast carcinomas.
Human Pathol. 2013;44:959-965.
30. Lien HC, Hsiao YH, Lin YS, et al. Molecular signatures of
metaplastic carcinoma of the breast by large-scale transcrip-
tional profiling: identification of genes potentially related to
epithelial-mesenchymal transition. Oncogene. 2007;26:7859-
7871.
31. Zhang Y, Toy KA, Kleer CG. Metaplastic breast carcinomas
are enriched in markers of tumor-initiating cells and epithe-
lial to mesenchymal transition. Mod Pathol. 2012;25:178-
184.
32. Carter MR, Hornick JL, Lester S, et al. Spindle cell (sarco-
matoid) carcinoma of the breast: a clinicopathologic and
immunohistochemical analysis of 29 cases. Am J Surg Pathol.
2006;30:300-309.
33. Yamaguchi R, Horii R, Maeda I, et al. Clinicopathologic
study of 53 metaplastic breast carcinomas: their elements and
prognostic implications. Hum Pathol. 2010;41:679-685.
34. Gobbi H, Simpson JF, Borowsky A, et al. Metaplastic breast
tumors with a dominant fibromatosis-like phenotype have a
high risk of local recurrence. Cancer. 1999;85:2170-2182.
35. Kochhar R, Howard EM, Umbreit JN, et al. Metaplastic
breast carcinoma with squamous differentiation: molecular
and clinical analysis of six cases. Breast J. 2005;11:367-369.
© American Society for Clinical Pathology