2012, Cilt 28, Sayı 2, Sayfa(lar) 134-141
Metaplastic Breast Carcinomas and Their Relationship with Basal-Like Phenotype
Aslı ÇAKIR, İpek Işık GÖNÜL, Ömer ULUOĞLU
Department of Pathology, Gazi University, Faculty of Medicine, ANKARA, TURKEY
Anahtar Kelimeler: Meme, Karsinom, Metaplazi
Metaplastik karsinom memenin nadir görülen yüksek
dereceli tümörüdür. Epitelyal ve mikst (epitelyal+mezenkimal)
tiplerden oluşur. Hormon reseptör ekspresyonu düşüktür. Çalışmalar,
metaplastik karsinomların genetik olarak bazal-benzeri profile sahip
olabileceğini belirtmektedir. Bu çalışmanın amacı, 11 metaplastik
karsinom olgusunun klinikopatolojik özelliklerini araştırmak ve
bazal-benzeri meme karsinomları ile benzerliklerini, morfolojik ve
immünhistokimyasal profillerine bakarak, değerlendirmektir.
Gereç ve Yöntem: On bir metaplastik karsinom olgusunun, ışık
mikroskopik morfolojik özellikleri değerlendirildi. Primer tümöre
ait kesitlerde, immünhistokimyasal olarak sitokeratin 5/6, sitokeratin
14 ve epidermal büyüme faktör reseptör ekspresyonları ile hormonal
Bulgular: Olguların dördü kondroid metaplazi gösteren karsinom,
üçü adenoskuamöz karsinom, ikisi skuamöz hücreli karsinom ve
ikisi karsinosarkom idi. Ortalama hasta yaşı 53, ortalama tümör çapı
5,1 cm idi. Tüm olgularda, tümörün nükleer derecesi ve histolojik
derecesi 3 idi. 10 büyük büyütme alanındaki ortalama mitoz sayısı 31
olarak saptandı. Dört olguda santral skar, beş olguda santral nekroz
ve yedi olguda coğrafik nekroz izlendi. Altı olguda tümör iter tarzda
büyüme gösteriyordu. Beş olguda karsinoma in situ saptanmadı. Lenf
bezleri değerlendirilen 10 hastanın 7'sinde aksiller metastatik lenf
bezi bulundu. İmmünhistokimyasal boyama yapılabilen 10 olgunun
7'si üçlü negatifti (östrojen reseptörü-, progesteron reseptörü-,
HER2-) ve 6'sında bazal-benzeri immünfenotip ile uyumlu olarak
sitokeratin 5/6 ve/veya epidermal büyüme faktör reseptörü pozitif idi.
Sitokeratin 14, yedi olguda pozitif saptandı.
Sonuç: Metaplastik karsinomlar, büyük çaplı, belirgin nükleer
pleomorfizm ve sık mitoz içeren yüksek dereceli tümörlerdir.
Hormon reseptörleri ile HER2 ekspresyonları nadir görülür ve
genellikle bazal-benzeri immünfenotip gösterirler.
Metaplastic carcinoma (MC) is a relatively rare tumor
of the breast, with an incidence of less than 1%1
encompasses a great histopathologic variation, which results
from the malignant epithelium undergoing metaplasia to
squamous cells or various mesenchymal elements2
World Health Organization (WHO) classifies MC as pure
epithelial or mixed (epithelial and mesenchymal) type1
According to the WHO, the epithelial type is sub-classified
into squamous cell carcinoma (SCC), adenocarcinoma
with spindle cell differentiation, and adenosquamous cell
carcinoma (ASCC), while the mixed type is sub-classified
into carcinoma with chondroid metaplasia (CwCM),
carcinoma with osseous metaplasia and carcinosarcoma1
Carcinomas showing chondroid or osseous metaplasia can
also be named as “matrix producing carcinoma” by others,
in which invasive carcinoma shows direct cartilaginous
and/or osseous stromal matrix differentiation without a
spindle cell component or osteoclastic giant cells3
Metaplastic carcinomas are generally known to present
with larger tumor size and higher tumor grade4,5.
They are usually negative for hormone receptors4,6.
The incidence of axillary lymph node involvement is low
but they show a greater risk of developing distant organ
metastasis4. Patients with MC generally have poorer
outcomes than with high-grade invasive ductal carcinoma
and they rarely benefit from conventional chemotherapy or
The key concept in the pathogenesis and development of
MCs is epithelial-mesenchymal transition (EMT). Lien et al.
reported that the EMT-related genes were differentially upregulated
in MC9. Osaka et al. proposed two progression
pathways of transition from the ductal component of the
adenocarcinoma to the sarcomatous component; either
transition directly from ductal to sarcomatous tissue or via
Breast carcinomas were recently classified into 4 types as
luminal, basal-like, normal breast-like and HER2 positive
according to their gene expression profile by using global
gene expression profiling10. Since basal-like and HER2
positive groups were reported to have aggressive clinical
behavior and poor prognosis11, it was thought that an extra
effort should be spent to diagnose these groups in a surgical
pathology routine. Therefore, an immunohistochemical
panel, proposed by Carey et al., including estrogen receptor
(ER), progesterone receptor (PR), human epidermal growth
factor receptor-2 (HER2), epidermal growth factor receptor
(EGFR) and cytokeratin 5/6 (CK 5/6), was widely accepted
for use in identifying breast carcinomas with basal-like immunophenotype as defined by cDNA microarrays12.
In the meantime, MCs have been shown to be a part of the
spectrum of basal-like breast carcinomas, since they usually
display a basal/myoepithelial and epithelial to mesenchymal
molecular make-up13,14, basal-like immunophenotype,
and triple negativity and often show expression of EGFR,
CK14 and CK5/615,16.
The aim of our study was to evaluate the light microscopic
histopathological features of 11 MCs that were diagnosed
in our institution between the years of 2006 and 2009
and to investigate their relationship to basal-like
A total of 468 breast carcinoma diagnoses were made at
the Pathology Department of our institution between
the years of 2006 and 2009. While all these cases were
histopathologically being re-evaluated for a graduation
thesis, 11 MCs were determined and included in this
study. The patient’s age and gender, tumor size, surgical
procedure type, the presence or absence of tumor invasion
in the nipple, skin and fascia of the breast tissue, ER, PR,
HER2 status of the tumor were all noted from the original
All hematoxylin eosin (HE)-stained tumor slides were
re-examined for the following morphological features to
determine the histological subtype according to the WHO
1. Grading was performed using the modified Bloom-
Richardson method, in which tubule formation of the
tumor cells, nuclear pleomorphism/atypia and mitotic
count were assessed17. Mitotic count was performed
on an Olympus BH2 light microscope, with a graticule at
40x magnification and in 10 high-power fields (HPFs).
Mitotic number was scored as 1 when it was between
0-7, 2 when between 8-14 and 3 when 15 or more.
2. Tumor growth pattern was assessed as “infiltrative” if
there was an irregular infiltration into the surrounding
parenchyma/fat or “pushing” if the tumor was well
3. The necrosis with its type was noted as “present” or
“absent”. Large irregular areas of tumor necrosis was
called “geographic necrosis” and necrosis in the middle
of the tumor, mostly because of the metabolic imbalance
between the cells and the vascular supply, was called
4. The presence or absence of carcinoma in situ (CIS) was
5. The presence of a central scar defined as a central
acellular area of tumor was looked for.
All HE-stained axillary lymph node slides were reviewed
for a metastatic component.
The formalin-fixed, routinely processed and paraffinembedded
tumor tissue blocks were available for 10 out
of the 11 cases. One case was a consultation, for which
only HE slides were present. Immunohistochemistry was
performed in tissue micro array (TMA) blocks constructed
for each case. The individual cases were represented with
four different 0,1 cm cores in the blocks. The TMA blocks
were stained with CK 5/6 (DAKO, Denmark, clone D5/16
B4, 1:100), CK 14(Spring bioscience, CA, USA, SPM 263,
1:100), and EGFR (DAKO, Denmark, clone E30, 1:100),
using the standard immunohistochemical techniques.
Diaminobenzidine was used as the chromogen and sections
were counterstained using Harris hematoxylin. For each
antibody, the percentage and the intensity of staining
were evaluated and recorded. Tumors showing no staining were considered as negative. Nuclear staining observed in
more than 1% of the tumor cells was regarded as positive
for ER and PR. HER2 over expression was evaluated semi
quantitatively and scores from 0 to 3 were given according
to the staining intensity and the percentage of positive
tumor cells for immunohistochemistry. The tumors with
an immunohistochemical score of 3 and/or with HER2/
CEP ratio equal to or more than 2.2 in fluorescent in situ
hybridization analysis were regarded as positive for HER2
We defined basal-like immunophenotype as triple negative
(TN) tumor with CK 5/6 and/or EGFR positivity according
to the criteria of Carey et al.12.
In this study, we included 11 cases of MCs for which eight
mastectomy and 2 lumpectomy specimens were present.
One case was a consultation for which we did not have
either paraffin blocks or the pathology report. All the
patients were female with an average age of 53 (range from
34 to 86) years. Grossly, the tumor diameter ranged from
1.4 to 28 cm in size with a mean of 5.1 cm. Microscopically,
6 cases were mixed type (4 were CwCM and 2 were carcinosarcoma) and 5 cases were pure epithelial type (3
were ASCC, 2 were SCC).
Morphological findings (Table I, Figure 1A-H)
All of the tumors were grade 3 with a nuclear score and
mitotic score of 3. The mean mitotic count was 31/10 HPFs,
ranging from 15 to 63. The score for tubule formation was
2 only in 2 cases (18.2%), and a score of 3 was given for the
remaining 9 cases.
Click Here to Zoom
|Figure 1: (A) Carcinoma with chondroid metaplasia. Chondroid island adjacent to the tumor cells with prominent nucleoli in solid
tumor (H&E, x200). (B) Carcinoma with chondroid metaplasia. Tumor has pushing margins and large necrosis on the left (H&E,
x200) (C) Geographic necrosis in the adenocarcinoma component (H&E, x400). (D) Adenosquamous carcinoma. Pleomorphic
adenocarcinomatous tumor cells intermingle with squamous cells with keratin pearls (H&E, x200) (E) Carcinosarcoma. Pleomorphic
epitheloid and spindle tumor cells (H&E, x100). (F) Carcinosarcoma. Spindle tumor cells have plenty mitosis and atypia (H&E, x400)
(G) Pure SCC with pushing margins (H&E, x40). (H) Pure SCC. Nests of pleomorphic, apoptotic tumor cells (H&E, x400).
Four (36%) of the 11 cases had a central scar, 5 (45%) had
central necrosis, and 7 (64%) had geographic necrosis.
Carcinoma in situ did not accompany 5 cases (45%). All of the CwCM cases, 1 case of ASCC and 1 case of SCC had
pushing margins while the remaining 5 cases (45%) had
Ten patients had an axillary lymph node biopsy and 7
(70%) of them had 1 to 26 metastatic lymph nodes. The
metastatic component was only epithelial in 6 cases (Figure
2A). A case of CwCM (case 1) had an epithelial dominant
metastatic deposit with chondroid matrix production in the
lymph node (Figure 2B). One of the carcinosarcomas (case
9) had both skin and fascia invasion and 1 ASCC (case 6)
had fascia invasion.
Click Here to Zoom
|Figure 2: Axillary lymph node metastasis. (A) Adenosquamous carcinoma (case 7). Both squamous and adenocarcinomatous components
can be seen (H&E, x100. Inset: H&E, x200). (B) Carcinoma with chondroid metaplasia (case 1). Both adenocarcinoma and chondroid
matrix can be seen (H&E, x40. Inset: H&E, x100).
Immunohistochemical findings (Table II, Figure 3A-C)
Immunohistochemical staining was performed in 10 cases.
Cytokeratin 5/6 was positive in all cases except case 1
(90%). Cytokeratin 14 was expressed in all 4 cases of the
CwCM, in one ASCC, in one carcinosarcoma and in one
SCC (70%). Epidermal growth factor receptor was positive
in half of cases (3 CwCM, 1 ASCC and 1 SCC). Estrogen
receptor and HER2 were negative in 9 cases (90%). PR was
negative in 8 (80%) cases.
Click Here to Zoom
|Figure 3: (A) Positive cytoplasmic staining for CK 5/6 (x100),
(B) Positive cytoplasmic staining for CK 14 (x100), (C) Positive
membranous staining for EGFR (x100).
Seven cases (70%) had TN hormonal status. Out of
these, 6 were positive for cytokeratin 5/6 and/or EGFR
and these were found to be consistent with basal-like
Metaplastic carcinoma is a heterogeneous group of
neoplasms, characterized by squamous, spindle cell,
and/or mesenchymal metaplasia/differentiation composed
of numerous distinct histological entities with or without
a conventional adenocarcinomatous component. Since
MCs are rare, comprising less than 1% of invasive breast
neoplasms, the reported data are relatively limited. We
analyzed 11 cases of MC, including 4 CwCM, 3 ASCC, 2
carcinosarcoma and 2 SCC cases by morphological and
immunohistochemical evaluations in this study to better
understand this rare but heterogeneous tumor category.
All patients in this study were female and the mean patient age was 53 years. Grossly, the tumor size ranged from 1.4
to 28 cm with a mean value of 5,1 and a median of 3,5 cm,
similar to other studies that have demonstrated that most
MCs were larger than 2 cm4-6,19. One study found that
tumor size was best correlated with prognosis2, whereas
this was not true in another study20.
All of the tumors we analyzed in the study were grade 3 and
the nuclear score was also 3 with the presence of pleomorphic
and atypical nuclei. The lesions were frequently solid and
only 2 of them had a tubule score of 2. The tumors were rich
in mitotic figures with an average mitotic count of 31/10
HPFs. The histopathological features observed in our series
are similar to the description in the previous studies4,5,7,15,16,21,22. In addition, 3 cases had a central scar, 5
had central necrosis, 7 had geographic necrosis and 6 had a
pushing growth pattern. In two studies, 43% and 64% of the
tumors respectively were purely invasive MCs with no insitu
component21,23. Similarly, we did not observe CIS
in 5 cases (45%) in our series. High histological grade, large
tumor size, the presence of frequent geographic necrosis
and low CIS rates may indicate that MCs grow rapidly.
The expression of hormone receptors and HER2 have
been reported to be low in MC’s5-7. Estrogen receptor
positivity was ranging from 0 to 19.2%, PR positivity was
0 to 35.7%, HER2 expression was 0 to 15.7% and TN was
80.4 to 100%14,15,21-27. Jung et al. also indicated that
frequency of a TN status was higher in MCs than invasive
ductal carcinomas28. Similarly, we found only 1 case
to be positive for ER, only 2 cases to be PR- positive and
HER2 over expression to be present in only one SCC.
Seventy percent of MCs, including all of the CwCM and
carcinosarcoma cases, were TN.
Metaplastic carcinomas are thought to develop through
a phenotypic transformation of epithelial cells into basal/
myoepithelial cells which then transform into carcinoma
and sarcoma25. Cytokeratin 5/6 and CK14 are basal
keratins and their expressions suggest a phenotype of EMT.
Wang et al. showed that CK5/6 and CK14 had a significant
association with a diagnosis of MC and that CK5/6 was
more sensitive than CK1425. In our study, 9 cases (90%)
were positive for CK5/6 and 7 cases (70%) were positive
for CK14. Only 1 CwCM lacked CK5/6 expression but this
case expressed CK14. Therefore, all of our cases showed
positivity for basal keratins, either CK5/6 or CK14.
Epidermal growth factor receptor, which is a member of the
ErbB family of transmembrane tyrosine kinase receptors,
is a sensitive marker (100%) for identifying MCs, but has a
low specificity (19,2%)22. Metaplastic carcinomas feature
over expression and amplification of EGFR protein, at rates of 57-83,3% and 26-34%, respectively16,25,27,29. It
has been also shown that EGFR immunohistochemical
expression correlates with EGFR amplification30. We
found that 50% of our cases (3 CwCM cases, 1 ASCC case
and 1 SCC case) showed immunohistochemical expression
of EGFR; and 2 carcinosarcoma cases (100%) lacked
EGFR expression. Although MCs have reported to have
high levels of expression and amplification of EGFR, they
were shown to lack EGFR activating mutations16,29.
Therefore it is not clear whether EGFR tyrosine kinase
inhibitors are effective for the treatment of MCs. For the
next step of the study, we are planning to extend the series
and add molecular methods to look for the amplification of
the gene for EGFR.
Recent studies demonstrated that regardless of the type of
metaplastic elements, MCs showed basal-like phenotype,
ranging from 91% to 100%, which was confirmed by both
expression array analysis and immunohistochemistry13,14,25,31. In this study, 6 cases (60%) showed basal-like
immunophenotype, which included all carcinosarcomas
and 3 out of 4 CwCM cases.
Basal-like breast carcinomas have been observed to possess
specific histopathological features such as high-grade nuclei,
high mitotic rate, lack of well-formed ductal structures,
presence of central and geographic necrosis, central scar
and pushing tumor borders32,33. When we look for
the presence of these morphological features of basal-like
phenotype in MCs showing basal-like immunophenotype,
the high nuclear pleomorphism (100%), high mitotic
rate (100%) and lack or scantiness of ductal structures
(100%) were the most consistent features. Accordingly, all
basal-like MCs were histological grade 3. Other common
features were geographic necrosis (66.7%), which was
most frequently seen in CwCM cases, and pushing tumor
borders (50%). Most of the MCs with geographic necrosis
had basal-like immunophenotype (57%). On the other
hand, central necrosis (33.3%) and central scar (16.7%)
were less common. There was no CIS component associated
with invasive carcinoma in half of the basal-like MCs.
Axillary lymph node involvement in MCs has been
documented to be low in previous reports, with an
incidence of 15-36.3%4,5,20,22,31. However, two
groups reported that more than half of their patients had
axillary lymph node metastases15,26. In addition, in
their series of 12 MC cases, Wang et al. found that all their
tumors had axillary lymph node involvement25. In our
study of 10 patients, 7 (70%) were found to have axillary
lymph node metastasis. The histological subtypes of the
primary tumor in the lymph node positive patients were
CwCM in 3 cases, ASCC in 2 cases, carcinosarcoma in 1 case and SCC in 1 case. The nodal metastases demonstrated
malign glandular and/or squamous elements except in a
case of CwCM (case1), which showed chondroid matrix
production within adenocarcinoma. This finding may also
support the idea that EMT occur in both primary tumor
and nodal metastases of MCs8 .
Patients with MC are thought to exhibit a poorer outcome
than patients with invasive ductal carcinoma, invasive
lobular carcinoma and TN invasive ductal carcinoma5,6,19,28. There is no consensus on the prognosis of
MC subtypes worldwide. Oberman et al. and Okada et
al. observed that no significant difference was present
in clinical outcome among their patients with different
MC subtypes2,6. On the other hand, Yamaguchi et al.
indicated that high grade spindle cells in MCs may be
important with respect to poor prognosis34. Generally,
prognosis of MCs is determined by tumor stage at the time
In conclusion, MCs tend to have large tumor size, high
histological grade, prominent nuclear pleomorphism and
plenty of mitotic figures morphologically. All cases in
this study expressed either one of the basal keratins. The
majority of the cases were found to have TN hormonal
status and more than half of the cases had a basal-like
immunophenotype. Besides having high scores for the each
parameter of the conventional grading schema (nuclear
pleomorphism, tubule formation and mitosis), the presence
of geographic necrosis is another morphological feature
of basal-like breast carcinoma that was also commonly
detected in MCs.
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