Content uploaded by Gary Tse
Author content
All content in this area was uploaded by Gary Tse on Dec 02, 2015
Content may be subject to copyright.
REVIEW
Spindle cell lesions of the breast—the pathologic differential
diagnosis
Gary M. K. Tse Æ Puay Hoon Tan Æ Philip C. W. Lui Æ
Thomas C. Putti
Received: 4 June 2007 / Accepted: 7 June 2007 / Published online: 18 July 2007
Springer Science+Business Media, LLC 2007
Abstract Spindle cell lesions of the breast represent an
interesting diagnostic problem, as the differential diagnoses
are wide. Diagnosing this is particularly problematic but
important when encountered in a needle core biopsy, as
treatments of different entities are different. In the histo-
logic assessment of spindle cell lesions, the simplified
approach is to evaluate the spindle cells and the accom-
panying epithelial cells. In the biphasic lesions with
predominance of spindle cells with benign epithelial
component, fibroepithelial lesions including fibroadenomas
and phyllodes tumors are the most common, followed by
pseudoangiomatous stromal hyperplasia, hamartoma and
adenomyoepithelioma. For biphasic lesions with predomi-
nance of spindle cells with malignant epithelial component,
the biphasic metaplastic carcinoma is likely. For mono-
phasic lesions with pure pleomorphic spindle cell only, the
monophasic metaplastic carcinoma is more common than
the rare primary sarcomas like malignant fibrous histiocy-
toma, angiosarcoma, and other high grade sarcomas. In
monophasic lesions with pure bland spindle cells only, the
possible lesions include fibromatosis, fibromatosis like
metaplastic carcinoma and other unusual conditions like
dermatofibrosarcoma protuberance. By careful searching
for the accompanying epithelial element, and with the aid
of appropriate clinical input and judicious use of immu-
nohistochemistry, many of these lesions can be confidently
diagnosed in the needle core biopsy, thus facilitating
appropriate treatments.
Keywords Breast Spindle cell Carcinoma Phyllodes
Introduction
Spindle cell lesions of the breast represent an interesting
diagnostic problem, as this encompasses a wide range of
lesions, many of which are uncommon and some are dis-
tinctly rare. Occasionally some common lesions including
reactive spindle cells changes and fibroadenomas may have
to be included in the consideration when one is dealing
with a spindle cell lesion, particularly in the setting of a
needle core biopsy (stereotactic, or vacuum assisted
mammotome). With the increasing use of core needle
biopsy as a diagnostic modality before definitive surgical
treatment, correct identification of individual spindle cell
lesion is crucial for proper management. With the advent of
more accurate imaging methods, together with proper
histopathologic interpretation and the judicial use of
ancillary methods like immunohistochemistry, most of the
entities making up this spindle cell lesions can be identified
with certainty, facilitating treatment planning.
Simplified approach to diagnosis
In the assessment of spindle cell lesions, the simple
approach is to evaluate two principle components of the
lesions to be assessed, namely spindle cells and epithelial
G. M. K. Tse (&) P. C. W. Lui
Department of Anatomical and Cellular Pathology, Prince of
Wales Hospital, The Chinese University of Hong Kong, Ngan
Shing Street, Shatin, NT, Hong Kong
e-mail: garytse@cuhk.edu.hk
P. H. Tan
Department of Pathology, Singapore General Hospital,
Singapore, Singapore
T. C. Putti
Department of Pathology, National University of Singapore,
Singapore, Singapore
123
Breast Cancer Res Treat (2008) 109:199–207
DOI 10.1007/s10549-007-9652-2
cells. The spindle cells can be bland or can be pleomorphic,
and they may also be mixed with epithelial component,
which again may be benign, or may be malignant. Thus in
this simplified approach, the spindle cell lesions can be
divided into 4 groups, as follows:
1. Biphasic lesions with predominance of spindle cells
with benign epithelial (ductal) component
2. Biphasic lesions with predominance of spindle cells
with malignant epithelial (ductal) component
3. Monophasic lesions with pure pleomorphic spindle
cell only
4. Monophasic lesions with pure bland spindle cell only
Using this simplified approach, one can start considering
the various entities in the diagnostic workup.
In the biphasic lesions with predominance of spindle
cells with benign ductal component, fibroepithelial lesions
including fibroadenomas and phyllodes tumors are the
most common lesions. Other lesions that one may have to
consider include pseudoangiomatous stromal hyperplasia
(PASH), hamartoma and adenomyoepithelioma. For
biphasic lesions with predominance of spindle cells
with malignant epithelial (ductal) component, metaplastic
carcinoma, particularly the biphasic type is the main lesion
to consider in this category. For monophasic lesions with
pure pleomorphic spindle cell only, the monophasic type of
metaplastic carcinoma has to be considered. Other lesions
to consider include sarcomas like malignant fibrous
histiocytoma (MFH), angiosarcoma, and other high grade
sarcomas. In the last category of monophasic lesions with
pure bland spindle cells only, the possible lesions include
fibromatosis, fibromatosis like metaplastic carcinoma
and other unusual conditions like dermatofibrosarcoma
protuberance (DFSP).
In the following discussion, some of these entities will
be discussed in some details, followed by an overview of
the role of immunohistochemistry in assisting the differ-
ential diagnosis. It is prudent to point out that a similar
diagnostic paradigm has been reported previously [1], and
the listing in this review is by no means exhaustive, as only
the more common lesions that one encounters in routine
daily practice are included. The most important concept is
to bear in mind that spindle cell lesions in the breast do not
necessarily imply a stromal lesion, and it is always crucial
to search diligently for epithelial element that is intermixed
with the spindle cell component, as the diagnosis will be
altered.
Fibroepithelial lesions
This group of lesions characteristically shows integral
epithelial and stromal elements that are intimately related,
and comprises fibroadenoma and phyllodes tumors. The
common histologic feature is expansion of the periductal
stromal tissue resulting in compression of the ductal ele-
ment giving rise to the typical intracanalicular appearance,
with the stroma showing typical myxoid appearing spe-
cialized stroma [2]. In the literature, there is considerably
more interest in evaluating and predicting the behavior of
phyllodes tumor [3] than fibroadenoma, which is consid-
ered benign.
Fibroadenoma
Fibroadenoma is probably the commonest breast ‘‘tumor’’
that any surgical pathologist encounters, and as such
requires little discussion. It is of interest to point out that
within a fibroadenoma, many changes particularly of the
epithelium may occur, and most of these changes are of
little significance. These changes include mild to moderate
duct hyperplasia, apocrine metaplasia and sclerosing
adenosis (10–40%), florid epithelial hyperplasia and cyst
formation (5–10%), calcifications, PASH-like changes.
Papilloma formation and smooth muscle in the stroma are
less common (1–5%). Significant lesions including atypical
epithelial hyperplasia (ductal or lobular), ductal or lobular
carcinomas (in situ or invasive) are much less common and
the incidence is much less than 1% [4]. What is more
important is the concept of complex fibroadenoma, which
is believed to incur a slightly higher relative risk for cancer
for as long as 20 years [5]. A fibroadenoma is considered
complex if it possesses any of the following features: (1)
cyst formation >3 mm, (2) sclerosing adenosis, (3) epi-
thelial calcification, and (4) papillary apocrine metaplasia.
These variations in morphology may be readily identified
in the setting of a needle core biopsy, or may only be
present focally, and hence detected in the excision speci-
men. The etiology of fibroadenoma is unclear, but may be
related to hormone, and interestingly, use of cyclosporine
therapy, and may involve the transforming growth factor-
beta (TGF-b)[6].
Phyllodes tumor
Phyllodes tumor is uncommon, being much less frequent
than fibroadenoma. The size may be larger, age of
incidence is in general about 15–20-years older than
fibroadenoma [3]. Microscopically, phyllodes tumor is
characterized by variable degree of stromal proliferation,
resulting in distortion of the architecture to give a leaf like
pattern. In general, the stromal cells tend to show increased
cellularity, nuclear crowding and atypia, increased mitotic
activity and stromal overgrowth (absence of epithelial
200 Breast Cancer Res Treat (2008) 109:199–207
123
element in the expanded stroma within a low power field).
The diagnosis of phyllodes tumor can range from malig-
nant to benign. A malignant diagnosis is made when there
is stromal hypercellularity, significant stromal cell atypia
or nuclear pleomorphism, the presence of stromal over-
growth or a malignant heterologous elements (osteoid or
chondroid), and increased mitotic activity (3–4 per 10 high
power fields) (Figs. 1, 2), whereas a benign diagnosis is
made when all these features are absent. The lesion is
labeled as borderline malignant if some but not all of these
features are present [7–12]. Irrespective of the degree of
malignancy of the phyllodes tumor, there is always the
presence of benign epithelial component, being lined by an
intact layer of myoepithelium, recapitulating the normal
ductal lobular architecture. The clinical behavior of this
group of lesion varies, benign phyllodes tumor tends to
recur but not metastasize, whereas both can occur in the
borderline and frankly malignant groups. Other histologic
changes may occur within phyllodes tumors, and they are
independent of the grading of the lesions, and are hence of
histologic interest only. Epithelial change of hyperplasia of
usual type is common (30–74%)[8, 12], with atypical
hyperplasia being much less common (1.5–4%) and higher
grade epithelial lesion occurring in less than 1% of cases.
Within the stroma, multinucleated stromal giant cells and
PASH-like areas may be seen, but these are of no prog-
nostic implications [13, 14].
PASH
Pseudoangiomatous stromal hyperplasia (PASH) has been
described some twenty years ago as a benign proliferative
lesion with characteristic slit-like pseudovascular space
lined by spindle cells (myofibroblasts) that resemble
endothelial cells in a background with keloid fibrosis [15].
Since then PASH has been described in many benign and
malignant breast lesions including carcinoma, hamartoma,
fibroadenoma and phyllodes tumors [8, 16, 17]. PASH can
also occur in a nodular form without association with other
breast lesions (Figs. 3,4). As such, this form is much more
uncommon. Preoperative diagnosis on clinical and radio-
logic assessments alone is difficult as well. Fine needle
aspiration cytology is also not useful [18]. Thus in a core
needle biopsy with bland spindle cells lining apparent
vascular spaces, PASH should be borne in mind.
Fig. 1 A malignant phyllodes tumor with benign epithelial element
overlying pleomorphic spindle cells (H&E, ·100)
Fig. 2 The same lesion at higher magnification, showing the
pleomorphic spindle cells in greater details (H&E, ·400)
Fig. 3 Pseudoangiomatous stromal hyperplasia showing the presence
of slit like spaces lined by bland spindle cells. Benign epithelial
element is seen in the vicinity (H&E, ·100)
Breast Cancer Res Treat (2008) 109:199–207 201
123
Hamartoma
Hamartoma of the breast has a reported incidence of 0.1–
0.7% [19–21], but many consider this an under-estimation,
with the increasing use of mammography [17], more
hamartomas, which possess a specific imaging pattern, may
be identified. It is originally defined as a clinically discrete
nodule with varying amount of epithelial and fibrofatty
stroma. In the literature, a rigid set of histologic or diag-
nostic criteria has not been set, but most authors have al-
luded to features like the interlobular fibrosis (the presence
of lobules within a fibrotic stroma, which surrounds and
extends to between individual lobules and obliterates the
usual interlobular loose stroma), encapsulated fat (adipose
tissue within the densely fibrotic stroma) and sometimes
the presence of PASH like changes in the stroma [17, 21–
23]. It is however important to realize that all these his-
tologic changes are not specific, and awareness on the part
of the pathologist, particularly coupled with the finding of a
mammographic breast lump, is important in identifying this
lesion.
Adenomyoepithelioma
Adenomyoepithelioma of the breast is rare tumor, and it
usually presents as a palpable mass in patients over 50 years
of age. Histologically this lesion is characterized by a two
cell type pattern. The glandular cells are unremarkable,
whereas the cells forming the outer layer can be basaloid to
spindle in shape. These cells show clear to eosinophilic
cytoplasm, and represent the main bulk of the neoplastic cell
population. Mitoses are usually infrequent. The behavior of
this lesion is best considered to be of low malignant potential,
as recurrences may occur infrequently, and this lesion does
not metastasize [24–26].
Metaplastic carcinoma
Metaplastic carcinoma is a group of uncommon malig-
nancy of the breast, and the term usually denotes those
carcinomas with mixed carcinomatous and sarcomatoid
components, or with sarcomatoid component alone. While
some authors have classified metaplastic carcinoma into
various subgroups basing on the presence or absence of
sarcomatoid or carcinomatous components, heterologous
elements or osteoclastic giant cells [27–31], metaplastic
carcinoma can be simply grouped into biphasic (with both
sarcomatoid and carcinomatous elements) (Fig. 5)or
monophasic (sarcomatoid element only) (Fig. 6)[7, 32].
Despite the morphologic division, metaplastic carcinoma
as a whole is considered high grade and is of poor prog-
nosis [32, 34, 35]. Recently, a fibromatosis like variant has
been described [35, 36], and this variant is of better
prognosis, being prone only to local recurrence but is of
low metastatic potential (Fig. 7).
The biphasic metaplastic carcinoma falls into the cate-
gory of biphasic spindle cell lesions with predominance of
spindle cells with malignant ductal component; the
monophasic metaplastic carcinoma falls into the category
of monophasic spindle cell lesion with pure pleomorphic
single cells and the fibromatosis like metaplastic carcinoma
belongs to the monophasic spindle cell lesions with pure
bland spindle cells. For the biphasic and monophasic
subgroups, the clinicopathological parameters are similar
and may be discussed together. Clinically, the age,
Fig. 4 The same lesion at higher magnification, with the bland
spindle cells lining vascular like spaces (H&E, ·400)
Fig. 5 Metaplastic carcinoma of biphasic type, showing poorly
cohesive pleomorphic spindle cells mixed with more cohesive
malignant cells resembling high grade ductal carcinoma (H&E, ·200)
202 Breast Cancer Res Treat (2008) 109:199–207
123
presentation and other imaging features are no different
from other mammary carcinomas. The tumor size in one
series of 24 cases ranged from 1.3 cm to 11.5 cm with a
mean of 4.6 cm [32], and the incidence of axillary lymph
node metastasis at diagnosis was 40–56% [32, 37]. The
histologic features are very interesting. For the biphasic
metaplastic carcinoma, the sarcomatoid component usually
is high grade with plump, pleomorphic, poorly cohesive
cells with brisk mitoses and necrosis. In addition, heterol-
ogous elements including bone or cartilage can be seen in
about 17% of cases [29]. The carcinomatous component is
also usually high grade, but may show up as either infil-
trating duct carcinoma (adenocarcinoma) or squamous cell
carcinoma or even as carcinoma in situ, with generally
more showing infiltrating duct carcinoma than squamous
cell carcinoma [32]. Immunohistochemistry plays an
important role in the diagnosis of metaplastic carcinoma.
The sarcomatoid component usually co-expresses cyto-
keratin and vimentin, and the cytokeratin cocktail AE1/3
remains the most sensitive [32]. This profile is a pre-
requisite for diagnosing the monophasic type of meta-
plastic carcinoma. Recently, it has been reported that p63 is
also helpful in diagnosing metaplastic carcinoma as the
spindle cells (but not the ductal carcinomatous component)
will be positive [38, 39]. Another interesting observation of
both biphasic and monophasic metaplastic carcinoma is the
frequent absence of expression of hormone receptors
(estrogen and progesterone) as well as HER2 oncogene,
and a significant proportion of metaplastic carcinomas
show EGFR gene amplification and over-expression [40],
and this may have significant treatment implication,
particularly in the current era of targeted therapy.
The fibromatosis like metaplastic carcinoma is an inter-
esting entity that one has to consider when dealing with
monophasic spindle cell lesions with pure bland spindle
cells. As its name suggests, the histomorphology of this
lesion resembles fibromatosis, with mostly rather bland
looking spindle cells growing in an infiltrative manner. In
some cases (up to 66% in one series [35]) focal cohesive
(epithelial) areas are seen, but the spindle cell population
remains dominant. The majority of the spindle tumor cells
co-expressed AE1/3 and vimentin and are negative for
hormone receptors and HER 2 [36]. This profile is very
similar to all other high grade metaplastic carcinoma. The
prognosis of this group is significantly different, however, as
about 20% of this fibromatosis like metaplastic carcinoma
recurred, and the metastatic rate was only 4% [35, 36].
Sarcomas of the breast
Primary sarcomas of the breast are rare, even in compari-
son to phyllodes tumors and metaplastic carcinoma. In
general, the prognosis of breast sarcomas is poor, with an
overall survival rate of about 60% [41, 42]. Both local
recurrences and distant organ metastases are significant
problems, occurring in 40–60% of cases [41–43], even
though lymph node metastases are distinctly uncommon
[43, 44]. In the following discussion, only the more com-
mon types of primary breast sarcomas will be discussed.
Angiosarcoma
Angiosarcoma is the most common primary breast sar-
coma, and can be divided according to the etiology, into
three groups:
Fig. 6 Metaplastic carcinoma of monophasic type, showing poorly
cohesive pleomorphic spindle cells (H&E, ·200)
Fig. 7 Fibromatosis like metaplastic carcinoma showing poorly
cohesive spindle cells with mild pleomorphism (H&E, ·200)
Breast Cancer Res Treat (2008) 109:199–207 203
123
1. those that arise de novo
2. those that arise after irradiation of the breast, and the
angiosarcoma may be confined to the skin, or may
affect both the skin and the breast. The interval of
onset is usually shorter than Stewart Treves syndrome
(about 5 years) and there is usually no history of
mastectomy and lymphedema is absent [45, 46]
3. Stewart Treves syndrome, angiocarcoma that is related
to chronic lymphedema and radiotherapy, is usually
highly aggressive and arising in the ipsilateral
extremity about 10 years after mastectomy [47]
Angiosarcoma usually presents as soft friable mass
with bluish discoloration; although the sizes are variable,
they are usually quite large on presentation, averaging
about 5 cm. Histologically they are divided into 3 grades
[48]. Grade 1 (well differentiated) tumors show well
formed vascular channels lined by mildly pleomorphic
endothelial cells, with minimal atypia and forming large
and open vascular spaces. Grade 2 tumors show focal
areas of cellular proliferation, the endothelial cells may
form papillary projections, with some mitotic activities
and rare solid/spindle cell areas (Fig. 8). Grade 3 (poorly
differentiated) tumors show mostly solid areas, and the
endothelial cells show prominent nuclear pleomorphism
and mitotic activity. Grading of angiosarcoma is impor-
tant as the survival rate drops significantly from Grade 1
to Grade 3 tumors.
Other sarcomas
Other sarcomas of the breast are very rare, and in general
have poor prognosis [40, 42]. This group of malignancy is
characterized by local recurrences and visceral organs
metastases [49, 42, 43], but not lymph node metastases.
Malignant fibrous histocytoma and fibrosarcoma are
probably the most common sarcomas within this group.
There may be a previous history of irradiation to the chest
wall (post mastectomy), and most of the tumors are solitary.
In the biopsy the spindle cells may be arranged in fascicles
or with a herringbone pattern, mild pleomorphic nuclei and
low mitotic rate if low grade, or bizarre spindle cells with
highly pleomorphic nuclei, multinucleated tumor giant cells,
with areas of necrosis if high grade (Fig. 9)[40, 49]
Liposarcoma within a needle core biopsy more likely
represents part of a malignant phyllodes tumor than a
primary liposarcoma of the breast [50]. The histology is
similar to liposarcoma found elsewhere, with lipoblasts
showing scalloped, irregular and hyperchromatic nuclei
with sharply defined intracytoplasmic vacuoles of fat,
and as in other areas, myxoid, well differentiated and
pleomorphic variants have been described [51].
Other sarcomas are exceedingly rare, including leiomy-
oma, rhabdomyosarcoma, chondrosarcoma, and malignant
peripheral nerve sheath tumor. The histologic features are
similar to those occurring in other parts of the body.
Uncommon Conditions that may give rise to spindle cell
pattern
1. Spindle cell ductal carcinoma in situ. While most
ductal carcinoma in situ is readily identified in his-
tology, very rarely in the setting of a core biopsy, this
condition may cause some confusion. This has the
rather characteristic demographic feature of occurring
in elderly patients with a long standing history.
Fig. 8 Angiosarcoma in a needle core biopsy specimen, showing
anastomosing vascular spaces lined by mildly pleomorphic endothe-
lial cells that are neoplastic (H&E, ·100)
Fig. 9 Malignant fibrous histiocytoma showing highly pleomorphic
spindle cells (H&E, ·200)
204 Breast Cancer Res Treat (2008) 109:199–207
123
Histologically the spindle cells are bland looking, and
despite the spindling, are somewhat cohesive (Fig 10).
The cardinal features are the presence of loose chro-
matin pattern and granular eosinophilic cytoplasm,
characteristic of those with neuroendocrine differenti-
ation. These may also be association with mucinous
carcinoma [52, 53].
2. Dermatofibrosarcoma protuberance (DFSP) (Fig. 11).
This is an uncommon cutaneous nodular tumor with a
tendency to local recurrence but metastasis is uncom-
mon. DFSP in the breast is rare, with only a few cases
reported, and this has been reported in young women
as well as in children [54–56]. The diagnosis of DFSP
is not difficult if the pathologist is aware of this pos-
sibility. The most useful hint will be the identification
of the lesion in the dermal or superficial subcutaneous
tissue plane superficial to the breast parenchyma.
Differentiation criteria and the role
of immunohistochemistry
To aid the appropriate diagnosis of spindle cell lesions in a
biopsy setting, awareness of the clinical setting, careful
examination of the H&E sections as well as immunohis-
tochemistry are all very helpful.
A previous history of breast carcinoma raises the
possibility of primary breast sarcoma post irradiation, and
in patients with a previous history of metaplastic carci-
noma, the spindle cell lesion may represent recurrence.
Diligent examination of the histologic sections is also
useful. Careful scrutiny for benign epithelial element sug-
gests a diagnosis of fibroepithelial lesions including
fibroadenoma and phyllodes tumors, whereas identification
of carcinomatous component favors a diagnosis of meta-
plastic carcinoma. The presence of areas that are somewhat
cohesive is suggestive of monophasic metaplastic carci-
noma or even spindle cell ductal carcinoma in situ. The
identification of osseous differentiation or lipoblasts is
more likely to suggest malignant phyllodes tumor or
metaplastic carcinoma with heterologous element rather
than primary osteosarcoma or liposarcoma.
Immunohistochemistry is of immense value in the elu-
cidation of the nature of a spindle cell lesion. Epithelial
markers for cytokeratin like AE1/3 or CAM5.2 are useful to
confirm the epithelial nature of some of the differential
diagnosis as spindle cell DCIS will show the characteristic
perinuclear dot-like positivity, and in metaplastic carcinoma
the malignant spindle cells will also be focally positive,
particularly for the more cohesive areas. Vimentin will give
the opposite staining pattern, highlighting all the true
mesenchymal spindle cell lesions, but not the carcinoma,
except for metaplastic carcinoma, in which the spindle cells
co-express cytokeratin and vimentin. p63 has been reported
to be specific for the spindle cells of metaplastic carcinoma
[38, 39]. In addition p63 can serve as a myoepithelial
marker, confirming the benign epithelial element with
myoepithelial cells in fibroepithelial lesions, including both
fibroadenoma and phyllodes tumor of all grades.
To delineate the differentiation of the primary mammary
sarcomatous lesion, differentiation specific markers may be
helpful, including CD31 for vascular differentiation, S100 for
chondroid and lipomatous differentiation, smooth muscle
actin for leiomyomatous differentiation and myogenin for
rhabdomyomatous differentiation. CD34 can also be used to
identify vascular lesion, DFSP and PASH [57].
Fig. 10 Spindle cell ductal carcinoma in situ showing rather
cohesive malignant cells with some suggestion of spindling (H&E,
·400)
Fig. 11 Dermatofibrosarcoma protuberance with rather bland spindle
cells alone in an irregular to storiform pattern of arrangement (H&E,
·100)
Breast Cancer Res Treat (2008) 109:199–207 205
123
Summary
The approach to spindle cell lesions of the breast remains
full of pitfalls. Careful histologic examination to identify
epithelial element, focal cohesiveness within the spindle
cell area and heterologous elements is of great value.
Judicious use of immunohistochemistry will allow correct
diagnosis to be made in the majority of cases.
References
1. Al-Nafussi A (1999) Spindle cell tumours of the breast: practical
approach to diagnosis. Histopathology 35(1):1–13
2. Lerwill MF (2004) Biphasic lesions of the breast. Sem Diagn
Pathol 21(1):48–56
3. Tse GMK, Tan PH (2005) Recent advances in the pathology
of fibroepithelial tumours of the breast. Curr Diagn Pathol 11:
426–434
4. Kuijper A, Mommers E, van der Wall E, van Diest PJ (2001)
Histopathology of fibroadenoma of the breat. Am J Clin Pathol
115(5):736–742
5. Dupont WD, Page DL, Parl FF, Vnencak-Jones CL, Plummer
WD Jr, Rados MS, Schuyler PA (1994) Long-term risk of breast
cancer in women with fibroadenoma. N Eng J Med 331(1):10–15
6. Sangthawan P, Fox J, Atkins RC, Kerr PG (2002) Increased
incidence of benign breast disease in female renal transplant
patient receiving cyclosporine. ANZ J Surg 72(3):222–225
7. Elston CW, Ellis IO (1998) The breast. In: Systemic pathology,
vol. 13, 3rd edn. Churchhill Livingstone, Edinburgh
8. Tan PH, Jayabaskar T, Chuah KL, Lee HY, Tan Y, Hilmy M,
Hung H, Selvarajan S, Bay BH (2005) Phyllodes tumours of the
breast. The role of pathologic parameters. Am J Clin Pathol
123(4):529–540
9. Tse GM, Putti TC, Kung FY, Scolyer RA, Law BK, Lau TS, Lee
CS (2002) Increased p53 protein expression in malignant mam-
mary phyllodes tumours. Mod Pathol 15(7):734–740
10. Moffat CJ, Pinders SE, Dixon AR, Elston CW, Blamey RW, Ellis
IO (1995) Phyllodes tumours of the breast: a clinicopathological
review of thirty-two cases. Histopathology 27(3):205–228
11. Parkers SJ, Harries SA (2001) Phyllodes tumours. Postgrad Med J
77(909):428–435
12. Grimes MM (1992) Cytosarcoma phyllodes of the breast: histo-
logical features, flow cytometric analysis, and clinical correlation.
Mod Pathol 5(3):232–239
13. Tse GM, Law BK, Chan KF, Ma TK (2001) Multinucleated
stromal giant cells in mammary phyllodes tumours. Pathology
33(2):153–156
14. Powell CM, Cranor ML, Rosen PP (1994) Multinucleated stromal
giant cells in mammary fibroepithelial neoplasms. A study of 11
patients. Arch Pathol Lab Med 118(9):912–916
15. Vuitch MF, Rosen PP, Erlandson RA (1986) Pseudoangiomatous
hyperplasia of mammary stroma. Hum Pathol 17:185–191
16. Ibrahim RE, Sciotto CG, Weidner N (1989) Pseudoangiomatous
hyperplasia of mammary stroma. Some observations regarding its
clinicopathologic spectrum. Cancer 63(6):1154–1160
17. Tse GM, Law BK, Ma TK, Chan AB, Pang LM, Chu WC, Cheng
HS (2002) Hamartoma of the breast: a clinicopatholgical review.
J Clin Pathol 55(12):951–954
18. Lui PC, Law BK, Chu WC, Pang LM, Tse GM (2004) Fine-
needle aspiration cytology of pseudoangiomatous stromal
hyperplasia of the breast. Diagn Cytopathol 30(5):353–355
19. Charpin C, Mathonlin MP, Andrac L, Barberis J, Boulat J,
Sarradour B, Bonnier P, Piana L (1994) Reappraisal of breast
hamartomas. A morphological study of 41 cases. Pathol Res Pract
190(4):362–371
20. Linell F, Ostberg G, Soderstrom J, Andersson I, Hildell J,
Ljungqvist U (1979) Breast hamartomas. An important entity in
mammary pathology. Virchows Arch A Pathol Anat Histol
383(3):253–264
21. Fisher CJ, Hanby AM, Robinson L, Millis RR (1992)
Mammary hamartoma–a review of 35 cases. Histopathology
20(2):99–106
22. Daya D, Trus T, D’Souza TJ, Minuk T, Yemen B (1995)
Hamartoma of the breast, an underrecognized breast lesion. Am J
Clin Pathol 103(6):685–689
23. Jones MW, Norris HJ, Wargotz ES (1991) Hamartomas of the
breast. Surg Gynecol Obstet 173(1):54–56
24. Kiaer H, Nielsen B, Paulsen S, Sorensen IM, Dyreborg U, Blic-
hert-Toft M (1984). Adenomyoepithelial adenosis and low-grade
malignant adenomyoepithelioma of the breast. Virchows Arch A
Pathol Anat Histopathol 405(1):55–67
25. Eusebi V, Casadei GP, Bussolati G, Azzopardi JG (1987)
Adenomyoepithelioma of the breast with a distinctive type of
apocrine adenosis. Histopathology 11(3):305–315
26. Loose JH, Patchefsky AS, Hollander IJ, Lavin LS, Cooper HS,
Katz SM (1992) Adenomyoepithelioma of the breast. A spectrum
of biologic behavior. Am J Surg Pathol 16(9):868–876
27. Wargotz ES, Norris HJ (1989) Metaplastic carcinomas of the
breast. I. Matrix-producing carcinoma. Hum Pathol 20(7):
628–635
28. Wargotz ES, Deos PH, Norris HJ (1989) Metaplastic carcinomas
of the breast. II. Spindle cell carcinoma. Hum Pathol 20(8):
732–740
29. Wargotz ES, Norris HJ (1989) Metaplastic carcinomas of the
breast. III. Carcinosarcoma. Cancer 64(7):1490–1499
30. Wargotz ES, Norris HJ (1990) Metaplastic carcinomas of the
breast. IV. Squamous cell carcinoma of ductal origin. Cancer
65(2):272–276
31. Wargotz ES, Norris HJ (1990) Metaplastic carcinomas of the
breast. V. Metaplastic carcinoma with osterolastic giant cells.
Hum Pathol 21(11):1142–1150
32. Tse GM, Tan PH, Putti TC, Lui PC, Chaiwun B, Law BK (2006)
Metaplastic carcinoma of the breast: a clinicopathological review.
J Clin Pathol 59(10):1079–1083
33. Christensen L, Schiodt T, Blichert-Toft M (1993) Sarcomatoid
tumours of the breast in Denmark from 1977 to 1987. A clini-
copathological and immunohistochemical study of 100 cases. Eur
J Cancer 29A(13):1824–1831
34. Kurian KM, Al-Nafussi A (2002) Sarcomatoid/metaplastic
carcinoma of the breast: a clinocopathological study of 12 cases.
Histopathology 40(1):58–64
35. Gobbi H, Simpson JF, Borowsky A, Jensen RA, Page DL. (1999)
Metaplastic breast tumours with a dominant fibromatosis-like
phenotype have a gihg risk of local recurrence. Cancer
85(10):2170–2182
36. Sneige N, Yaziji H, Mandavilli SR, Perez ER, Ordonez NG,
Gown AM, Ayala A (2001) Low-grade (fibromatosis-like)
spindle cell carcinoma of the breast. Am J Surg Pathol 25(8):
1009–1016
37. Khan HN, Wyld L, Dunne B, Lee AH, Pinder SE, Evans AJ,
Robertson JF (2003) Spindle cell carcinoma of the breast: a
case series of a rare histological subtype. Eur J Surg Oncol 29(7):
600–603
38. Koker MM, Kleer CG (2004) p63 expression in breast cancer: a
highly sensitive and specific marker of metaplastic carcinoma.
Am J Surg Pathol 28(11):1506–1512
39. Tse GM, Tan PH, Chaiwun B, Putti TC, Lui PC, Tsang AK,
Wong FC, Lo AW (2006) p63 is useful in the diagnosis of
mammary metaplastic carcinomas. Pathology 38(1):16–20
206 Breast Cancer Res Treat (2008) 109:199–207
123
40. Adem C, Reynolds C, Ingle JN, Nascimento AG (2006) Primary
breast sarcoma: clinicopatholgic series from the Mayo Clinic and
review of the literature. Br J Cancer 91(2):237–241
41. Reis-Filho JS, Milanezi F, Carvalho S, Simpson PT, Steele D,
Savage K, Lambros MB, Pereira EM, Nesland JM, Lakhani SR,
Schmitt FC (2005) Metaplastic breast carcinoma exhibit EGFR,
but not HER-2, gene amplification and overexpression: immu-
nohistochemical and chromogenic in situ hybridization analysis.
Breast Cancer Res 7(6):R1023–1035
42. Blanchard DK, Reynolds CA, Grant CS, Donohue JH (2003)
Primary nonphylloides breast sarcomas. Am J Surg 186(4):359–361
43. McGowan TS, Cummings BJ, O’Sullian B, Catton CN, Miller N,
Panzarellar T (2000) An analysis of 78 breast sarcoma patient
without distant metastases at presentation. Int J Radiat Oncol Biol
Phys 46(2):383–390
44. Pollard SG, Marks PV, Temple LN, Thompson HH (1990) Breast
sarcoma. A clinicopatholgic review of 25 cases. Cancer
66(1):941–944
45. Billings SD, McKenney JK, Folpe AL, Hardacre MC, Weiss SW
(2004) Cutaneous angiosarcoma following breast-conserving
surgery and radiation: an analysis of 27 cases. Am J Clin Pathol
28(6):781–788
46. Strobbe LJ, Peterse HL, van Tinteren H, Wijnmaalen A, Rutger
TJ (1998) Angiosarcoma of the breast after conservation therapy
of invasive cancer, the incidence and outcome. An unforeseen
sequela. Breast Cancer Res Treat 47(2):101–109
47. Clements WD, Kirk SJ, Spence RA (1993) A rare late compli-
cation of breast cancer treatment. Br J Clin Pract 47(4):219–220
48. Rosen PP, Kimmel M, Ernsberger D (1988) Mammary angio-
sarcoma. The prognostic significance of tumor differentiation.
Cancer 62(21):2145–2151
49. Barrow BJ, Janjan NA, Gutman H, Benjamin RS, Allen P,
Romsdahl MM, Ross MI, Pollock RE (1999) Role of readio-
therapy in sarcoma of the breast—a retrospective review of the
M.D. Anderson experience. Radiother Oncol 52:173–178
50. Powell CM, Rosen PP (1994) Adipose differentiation in cysto-
sarcoma phyllodes. A study of 14 cases. Am J Surg Pathol
18:720–727
51. Christensen L, Schiodt T, Blichert-Toft M, Hansen JP, Hansen
OH (1988) Sarcomas of the breast: a clinico-pathological study
of 67 patients with long term follow-up. Eur J Surg Oncol 14:
241–247
52. Tsang WY, Chan JK (1996) Endocrine ductal Carcinoma in situ
(E-DCIS) of the breast: A form of low grade DCIS with
distinctive clinicopatholgic and biologic characteristics. Am J
Surg Pathol 20(8):921–943
53. Tan PH, Lui GG, Chiang G, Yap WM, Poh WT, Bay BH (2004)
Ductal carcinoma in situ with spindle cells: a potential diagnostic
pitfall in the evaluation of breast lesions. Histopathology
45(4):343–351
54. Tsang AK, Wong FC, Ng PW, Loke SL, Tse GM (2005) Fine
needle aspiration cytology of dermatofibrosarcoma protuberans in
the breast: a case report. Pathology 37(1):84–86
55. Sandberg AA, Anderson WD, Fredenberg C, Hashimoto H
(2003) Dermatofibrosarcoma protuberans of breast. Cancer Genet
Cytogenet 142(1):56–59
56. Goldberg DJ, Maso M (1990) Dermatofibrosarcoma protuberans
in a 9-year-old child: treatment by MOHS micrographic surgery.
Pediatr Dermatol 7(1):57–59
57. Okoshi K, Ogawa H, Suwa H, Saiga T, Kobayashi H (2006) A
case of Nodular Pseudoangiomatous Stromal Hyperplasia
(PASH). Breast Cancer 13(4):349–353
Breast Cancer Res Treat (2008) 109:199–207 207
123
