Fibroepithelial Tumors of the Breast
Pathologic and Immunohistochemical Features and Molecular Mechanisms
Xiaofang Yang, MD, PhD; Dina Kandil, MD; Ediz F. Cosar, MD; Ashraf Khan, MD
 Context.—The 2 main prototypes of fibroepithelial
tumors of the breast include fibroadenoma and phyllodes
tumor (PT). Although both tumors share some overlapping
histologic features, there are significant differences in their
clinical behavior and management. Phyllodes tumors have
been further divided into clinically relevant subtypes, and
there is more than one classification scheme for PT
currently in use, suggesting a lack of consistency within
different practices. Accurate differentiation between fi-
broadenoma and PT, as well as the grading of PT, may
sometimes be challenging on preoperative core needle
biopsy. Some immunohistochemical markers have been
suggested to aid in the pathologic classification of these
lesions.
Objective.—To discuss the salient histopathologic fea-
tures of fibroepithelial tumors and review the molecular
pathways proposed for the initiation, progression, and
metastasis of PTs. Also, to provide an update on
immunohistochemical markers that may be useful in their
B reast cancer is the most common malignancy in women
of all ethnic groups, and it is the second most common
cause of cancer deaths in women in the United States. It is
estimated that 10% of women will develop detectable breast
lump(s) in their lifetime, half of which are malignant.1 The
standard treatment for breast cancer is complete surgical
resection with negative margins. Postoperative radiation,
and/or hormonal therapy and chemotherapy may be
needed, depending on the grade and stage of the tumor.2
Therefore, accurate preoperative pathologic diagnosis based
on the limited specimen from core needle biopsy (CNB) or
fine-needle aspiration biopsy is a critical step for the optimal
management of patients with breast lumps. Breast cancer
screening modalities, including mammogram, magnetic
resonance imaging, and self–breast examination and clinical
breast examination, are recommended for early cancer
detection, and they may also result in the identification of
Accepted for publication February 7, 2013.
From the Department of Pathology, University of Massachusetts
Medical School and UMass Memorial Medical Center, Worcester.
The authors have no relevant financial interest in the products or
companies described in this article.
Reprints: Ashraf Khan, MD, Department of Pathology, University of
Massachusetts Medical School, Biotech 3, One Innovation Drive,
Worcester, MA 01605 (e-mail: khana@ummhc.org).
Arch Pathol Lab Med—Vol 138, January 2014
differential diagnosis and outline the practice and experi-
ence at our institution from a pathologic perspective.
Data Sources.—Sources included published articles
from peer-reviewed journals in PubMed (US National
Library of Medicine).
Conclusions.—Fibroepithelial tumor of the breast is a
heterogenous group of lesions ranging from fibroadenoma
at the benign end of the spectrum to malignant PT. There
are overlapping histologic features among various sub-
types, and transformation and progression to a more
malignant phenotype may also occur. Given the significant
clinical differences within various subtypes, accurate
pathologic classification is important for appropriate
management. Although some immunohistochemical mark-
ers may be useful in this differential diagnosis, histomor-
phology still remains the gold standard.
(Arch Pathol Lab Med. 2014;138:25–36; doi: 10.5858/
arpa.2012-0443-RA)
other nonneoplastic and neoplastic breast lesions, including
fibroepithelial tumors.
Fibroepithelial tumors of breast, including fibroadenoma
and phyllodes tumor (PT), are biphasic neoplasms charac-
terized by proliferation of both epithelial and stromal
components. As illustrated in Figure 1, fibroadenoma and
PT, as well as various grades of PT, share some overlapping
morphology, but significant differences in pathologic
features and clinical behavior define various subsets of
fibroepithelial tumors. Fibroadenoma accounts for the vast
majority of benign breast tumors. Clinically, fibroadenomas
usually occur in younger women, ages 20 to 30 years, but
may also be seen in postmenopausal age groups. They are
slow-growing tumors, with a size of less than 3 cm, except
for rare giant fibroadenomas. The overall risk of developing
breast carcinoma in patients with a history of fibroadenoma
is low, varying from 1.5- to 2.6-fold compared with control
patients in different studies, and it may be higher in women
with a family history of breast cancer or in women with the
BRCA1 gene mutation, justifying excision of complex
fibroadenoma in women at high risk for developing cancer.
Both invasive and in situ carcinoma may occur in
fibroadenoma.3 The incidence of carcinoma arising within
a fibroadenoma is reported to be from 0.1% to 0.3%.
Although ductal and lobular carcinomas in situ occur with
equal frequency, most invasive carcinomas are reported to
be of lobular type.3–6 Phyllodes tumor is a rare fibroepithelial
Fibroepithelial Tumors of the Breast—Yang et al 25
Figure 1. Clinicopathologic features of fibroadenoma and various grades of phyllodes tumor: although there are some overlapping histologic
features, significant clinicopathologic differences are evident. HPF, high-power field; Mets, metastases; PT, phyllodes tumor.

neoplasm accounting for less than 1% of all breast tumors at times mimic colloid (mucinous) carcinoma, especially in
and approximately 2.5% of fibroepithelial tumors of the fragmented biopsies. Cellular fibroadenoma with intracan-
breast.7 The clinical behavior and prognosis of PTs are quite alicular growth pattern can closely mimic benign phyllodes.
different from those of fibroadenoma. Patients with PT are The distinction is based on overall diffuse stromal cellularity,
usually 10 to 20 years older than patients with fibroadeno- which is sometimes accentuated around epithelial clefts in
ma, with a mean age of 44 years, and PT is often larger in the PT.14 In CNB specimens, this distinction can be
size than fibroadenoma.8 In view of the difference in challenging, but it is critical because of the different behavior
management and clinical behavior between fibroadenoma and clinical management for these 2 entities. In such cases,
and PT, accurate preoperative diagnosis is very important. surgical excision for better classification is recommended.
Overlapping histologic features and synchronous lesions Cellular stroma may also raise the possibility of other
may make this distinction challenging at times, especially in spindle cell neoplasms, including mammary myofibroblas-
limited samples on CNB.9–12 Fibroadenoma and PT, toma, fibromatosis, or spindle cell carcinoma. Epithelial
although similar in some respects, are thought to differ in alterations within fibroadenoma include squamous and
their molecular mechanisms with respect to tumor initiation apocrine metaplasia and various degrees of hyperplasia,
and progression. Various ancillary studies have been including atypical ductal and lobular hyperplasia.13 As
suggested to aid in the differentiation of fibroadenoma described earlier, invasive and in situ carcinoma may rarely
and PT, and also in the subclassification of PT into be seen associated with fibroadenoma (Figure 4).3–6,13,15
prognostically significant categories, such as benign, bor- Although fibroadenomas are considered innocuous, a recent
derline, and malignant. report showed that 22 of 172 PT patients (12.8%) had
previous fibroadenoma excisions,16 and 11 of 36 malignant
PATHOLOGY OF FIBROEPITHELIAL TUMORS
Fibroadenoma
On gross examination, fibroadenoma appears well cir-
cumscribed and firm in consistency, with a white-tan to gray
homogenous, smooth-cut surface (Figure 2). Microscopical-
ly, fibroadenomas show biphasic growth with ductular and
stromal proliferation; the latter may show a predominant
intracanalicular or pericanalicular growth pattern with
varying degrees of cellularity, but neither pattern is
prognostically important. As shown in Figure 3, common
histologic stromal patterns in fibroadenoma include diffuse
myxoid change, hyalinization, and increased cellularity, as in
cellular fibroadenoma; less frequently, foci of smooth
muscle differentiation may be seen in fibroadenoma in
addition to other stromal alterations, such as foci of
pseudoangiomatous stromal hyperplasia.13 These stromal
variations are important to keep in mind when evaluating Figure 2. Gross appearance of fibroadenoma showing a well-
such lesions in small CNBs because the myxoid stroma may circumscribed, white-tan to gray, homogenous, smooth-cut surface.
26 Arch Pathol Lab Med—Vol 138, January 2014 Fibroepithelial Tumors of the Breast—Yang et al
Figure 3. Histologic features of fibroadenoma with varying stromal alterations on hematoxylin-eosin stain: (A) diffuse myxoid change; (B)
hyalinization; (C) increased cellularity; and (D) smooth muscle differentiation (smooth muscle actin was strongly positive, confirming the
morphologic diagnosis) (original magnifications 3100).
PT cases (30.6%) had a history of fibroadenoma,17 raising
the possibility that some fibroadenomas may undergo
malignant transformation to PTs. Therefore, any atypical
epithelial proliferation or unusual stromal alterations within
a fibroepithelial tumor on a core needle biopsy should
warrant complete excision of the lesion for further
evaluation and to rule out associated malignant transfor-
mation or PT.
Phyllodes Tumor
Phyllodes tumor is primarily differentiated from fibroad-
enoma on histology by its characteristic leaflike pattern,
produced by the exaggerated intracanalicular stromal
proliferation and variably dilated ducts. Additional features
include stromal overgrowth, increased stromal cellularity,
and mitotic activity (Figure 5). On gross examination PT is
also as well delineated and circumscribed as fibroadenoma,
but the cut surface shows cleftlike spaces with interspersed
nodular stromal growth, and the color varies from tan to
yellowish gray (Figure 6, A). Large tumors may show areas
of hemorrhage and necrosis, and malignant PT may have a
fleshy sarcoma-like cut surface that is softer in consistency
than a fibroadenoma or benign PT (Figure 6, B).
Arch Pathol Lab Med—Vol 138, January 2014
Histologically, PTs are classified into different grades to
predict their prognosis and clinical behavior. Two-tier
(benign and malignant) and three-tier (benign, borderline,
and malignant; benign low-grade malignant and high-grade
malignant) grading systems for PTs have been proposed.
Since 1951, 3 categories have been used widely and adapted
by the World Health Organization. These include benign,
borderline, and malignant PT based on histologic parame-
ters, including stromal cellularity, nuclear atypia and degree
of pleomorphism, mitotic activity, tumor margin/border
(pushing or infiltrative), and stromal overgrowth. In a recent
study by Tan et al,18 only 3 histologic features (cellular
atypia, mitosis, and stromal overgrowth) and surgical
margins (together, the ‘‘AMOS criteria’’), but not stromal
hypercellularity or tumor border, were independent predic-
tive factors of clinical behavior in PTs. In cases with difficulty
in grading between benign and borderline or between
borderline and malignant PTs, surgical margin status and
ancillary tests as discussed below should be considered in
making the final diagnosis. In our unpublished study,84
among the 52 patients with PTs who presented to our
institution during a 12-year period, we found 64% of PTs
were benign, 25% were borderline (Figure 7), and 6% were
Fibroepithelial Tumors of the Breast—Yang et al 27
Figure 4. Carcinoma arising in fibroadenoma. A and B, Ductal carcinoma in situ, nuclear grade III with comedo necrosis associated with
fibroadenoma. C and D, Invasive ductal carcinoma, apocrine type arising within a fibroadenoma (hematoxylin-eosin stain, original magnifications
320 [A and C] and 3100 [B and D]).
malignant (Figure 8), consistent with other studies showing
approximately 50% to 70% benign tumors, 20% to 36%
borderline tumors, and 10% to 12% malignant tumors,19,20
although the range of the percentage for each grade varies
dramatically in other studies reviewed by Parker and
Harries.21 There are significant differences in the treatment
modalities between PTs and fibroadenomas. The mainstay
of treatment for PTs is surgical resection with wide margins,
whereas close follow-up or enucleation is acceptable for the
treatment of fibroadenomas. The local recurrence rate of PTs
is 10% to 18% with negative and positive resection margins,
respectively.22 In one study, a higher local recurrence rate
was also associated with marked stromal proliferation and
necrosis, but not with the tumor grade.22 However,
association of local recurrence rate with tumor grade was
observed in other studies, showing that recurrence occurred
in 8% to 10% of benign, 14% to 20% of borderline, and 29%
to 50% of malignant PTs.18,23 In addition to its tendency
toward local recurrence, PTs have malignant potential and
are capable of systemic spread. Overall, 9% to 27% of
malignant PTs can metastasize to distant organs through the
lymphovascular route and are associated with increased risk
of mortality.23–25 Benign PT may transform into a higher
grade and recur as borderline or malignant PT.
28 Arch Pathol Lab Med—Vol 138, January 2014
Role of Core Needle Biopsy in Diagnosis
of Fibroepithelial Tumors
Preoperative CNB has become an essential procedure for
optimal management of patients with breast lesions.
Although CNB can provide high negative and positive
predictive values, accurate diagnosis based on a limited
sample from CNBs can sometimes be challenging for
fibroepithelial neoplasms because of the heterogeneity and
overlapping features in these lesions.9,10,26 At times,
fibroadenoma can show moderate cellularity, mimicking
PTs, and PTs may have heterogeneous components similar
to benign fibroadenoma. Many studies have shown the
need for biomarkers, especially Ki-67, in addition to the
histologic features of these lesions for more accurate
preoperative evaluation.20,27 Our practice is that a cellular
fibroepithelial lesion on needle biopsy that is difficult to
classify as fibroadenoma or PT is best completely excised for
accurate classification.
MOLECULAR MECHANISMS AND ANCILLARY TESTS
IN FIBROEPITHELIAL TUMORS
There has been a wide range of interest in studying PTs
with respect to their grading, clinical behavior, prevalence,
Fibroepithelial Tumors of the Breast—Yang et al
Figure 5. Histologic features of benign phyllodes tumor: (A) characteristic dilated ducts with a leaflike pattern and exaggerated intracanalicular
stromal proliferation; (B) pushing margins; and (C and D) spindle cell stromal proliferation with no significant nuclear pleomorphism or mitoses
(hematoxylin-eosin, original magnifications 320 [A], 340 [B], 3100 [C], and 3200 [D]).

Figure 6. Gross appearance of borderline phyllodes tumor (PT) with cleftlike spaces, interspersed nodular stromal growth, and tan–to–yellowish
gray color change (A); malignant PT may have a fleshy sarcoma-like cut surface (B).
Arch Pathol Lab Med—Vol 138, January 2014 Fibroepithelial Tumors of the Breast—Yang et al 29
Figure 7. Histologic features of borderline phyllodes tumor (PT): (A) biphasic tumor similar to benign PT; (B) infiltrative margins with islands of
tumor cells invading the surrounding residual breast tissue; (C) stromal overgrowth with cellular stroma; and (D) moderate nuclear pleomorphism
and mitoses (averaging 6 per 10 high-power fields in this case) (hematoxylin-eosin, original magnifications 340 [A and B], 3100 [C], and 3400 [D]).

management, genetic/chromosomal alterations, pathogen-
esis, molecular mechanism or pathways, and biomarkers
distinguishing them from fibroadenomas, as well as in their
histologic subclassification. At the time of writing this
review, there were 1678 articles in the English literature,
including reviews from PubMed searches using the key
words ‘‘breast phyllodes’’ (1502 hits) and ‘‘breast phyl-
loides’’ (176 hits).
MOLECULAR MECHANISMS RELATED
TO THE DEVELOPMENT OF PTs
Insulin-like Growth Factor Signaling Pathway
Insulin-like growth factor (IGF) signaling pathway in-
volves 2 polypeptide hormones (IGF1 and IGF2), 2
transmembrane receptors (IGF1R and IGF2R), several
IGF-binding proteins (IGFBPs 1–6), and many downstream
effectors, such as PI3K and MAPK pathways.28 In general,
IGF plays an important role in regulating normal fetal cell
growth and differentiation, including mammary gland
development and involution,29,30 but also regulates cell
proliferation and apoptosis during tumorigenesis. Targeting
IGF1, IGFBPs, and the IGF1 receptor system for breast
cancer treatment is under investigation.31 IGF bioavailability
30 Arch Pathol Lab Med—Vol 138, January 2014
also can be regulated by IGFBP proteases. IGFBPs form
complexes with IGFs and may function as a latent reservoir
of IGFs. In breast tissues, IGF1 is thought to be produced in
the stroma in response to growth hormone, and it
synergizes with estrogen to promote terminal end duct
formation and mammary duct growth. IGF2 overexpression
in mice can induce mammary gland tumor growth after
multiple pregnancies. Both IGF1 and IGF2 can bind to IGF1
receptor, which is upregulated in the epithelia, and activate
downstream intracellular signaling pathways to promote
cell proliferation and inhibit apoptosis. Increased IGF
signaling has been found in various human tumors,
including breast cancers.
Interestingly, both IGF1 and IGF2 are overexpressed in
the stroma of fibroepithelial tumors.32 In PTs, they are found
particularly in the densely cellular stromal regions away
from the epithelium, although IGF1 expression appears
weak in malignant PTs. In contrast, no IGFs are expressed in
the epithelial component or in normal breast tissues.32 It is
believed that the epithelial-stromal interactions are required
for the normal development, differentiation, and function-
ing of the breast.33,34 Disruption of these interactions may
contribute to the development and progression of neoplasia.
Fibroepithelial Tumors of the Breast—Yang et al
Figure 8. Histologic features of malignant phyllodes tumor (PT): (A) biphasic tumor with stromal heterogeneity showing areas of more cellular
stroma (top right) and paucicellular areas (bottom left); (B) marked stromal overgrowth with cellular stroma showing marked nuclear pleomorphism;
(C) note the cellular and pleomorphic stroma in close approximation to the epithelial component; and (D) mitoses are easy to find (averaging 18 per
10 high-power fields, and Ki-67 index in this case was 20%) (hematoxylin-eosin, original magnifications 340 [A], 310 [B and C], and 3200 [D]).

It remains unclear how stromal IGFs interact with epithelial
IGFR1 in biphasic fibroepithelial tumors. Additionally,
moderate or strong IGF1 expression was associated with
moderate/strong b-catenin nuclear localization, suggesting
there is crosstalk between the IGF signaling pathway and
other signaling transduction pathways in the development
of PTs.
IGF2-Binding Proteins
IGF2-binding proteins (IGF2BPs, or IMPs 1, 2, and 3) are
a family of proteins that are related to the IGF signaling
pathway but have a role distinct from that of the previously
discussed IGFBPs. They were identified based on their
ability to bind to the 5 0 untranslated region of IGF2 mRNA
and enhance IGF2 translation.35,36 IMP1 and IMP3 proteins
are only expressed during embryogenesis to promote cell
growth and migration and are not expressed in normal adult
tissues, unlike IMP2 protein. Mechanistically, unlike IGFBPs
that directly bind IGFs, IGF2BPs (particularly IMP3) are
positive regulators for the stability and translation of IGF2
mRNA.36,37 IMP3 knockdown by siRNA in K562 human
leukemia cell line can inhibit the translation of IGF2 leader-3
mRNA without affecting the mRNA level of IGF2.38 IMP1
Arch Pathol Lab Med—Vol 138, January 2014
and IMP3 protein levels exert profound effects on cellular
adhesion and formation of invadopodia by stabilizing CD44
mRNA, suggesting that reexpression of IMPs in cancer cells
may promote tumor invasion and metastasis.39 Consistent
with the notion that reexpression of IMP3 in cancers is
important for cancer progression and invasion, knockdown
of IMP3 by siRNA is associated with decreased IGF2 protein
expression, increased apoptosis, reduced cell migration, and
invasion in several cell lines, including cervical carcinoma
cell line HeLa and breast cancer cell line MDA-231.40,41 In
the past decade, many studies have demonstrated that IMP3
expression can be used in diagnosis of malignancy and is
associated with a poor prognosis for various types of
cancers.42 In breast cancer, our previous study showed that
IMP3 may serve as a novel marker for triple-negative breast
cancers and is associated with a more aggressive pheno-
type.43 Interestingly, more recent data show that epidermal
growth factor receptor (EGFR) signaling can induce IMP3
expression, suggesting a complex regulatory pathway of IGF
signaling in breast tumorigenesis and progression.41,44
The molecular mechanisms by which IMP3 is expressed in
cancer cells remain unclear. In breast cancer cells, estrogen
receptor beta (ERb) appears to function as a transcriptional
Fibroepithelial Tumors of the Breast—Yang et al 31
repressor of IMP3.41 It is conceivable that epigenetic
mechanisms at the IMP3 promoter might also play a role
in its transcriptional reactivation, given that the IMP3
promoter possesses a CpG island that is potentially a target
for DNA demethylases and/or histone modification en-
zymes. Interestingly, IGFBP3 (not to be confused with
IGF2BP3 or IMP3), one member of the IGFBP family with
an opposite effect on cell growth compared with IMP3, also
has a CpG island at its promoter. IGFBP3 expression can be
reinduced by DNA demethylation agent 5-AZA-2 0 -deoxy-
cytidine treatment in hepatoblastoma cell line, and conse-
quently restoring IGFBP3 expression in these cells resulted
in reduced colony formation, migration, and invasion.45
Wnt–b-Catenin Signaling Pathway
Wnt–b-catenin signaling pathway also plays an important
role in normal mammary gland development and in
tumorigenesis of breast tissue.46 Wnt proteins are secreted
glycoproteins that regulate cell polarity and adhesion,
apoptosis, and tumorigenesis through direct and indirect
interactions with other cell signaling pathways.47 Deregula-
tion of the Wnt signaling pathway has been implicated in
many cancers and causes cytoplasmic b-catenin stabiliza-
tion, nuclear translocation, and activation of Wnt target
genes, including oncogenes c-myc, c-jun, Fra, and cyclin
D1. Interestingly, in an early study by Sawyer et al,32 in PTs
of the breast, abnormal stromal b-catenin nuclear translo-
cation was found in 72% of tumors. Meanwhile, aberrant
nuclear localization of b-catenin was not associated with
CTNNB1 (gene encoding b-catenin) mutations or loss of
heterozygosity of tumor suppressor gene APC, but it was
associated with increased Wnt5a expression in the epithe-
lium and, to a lesser extent, with Wnt2 overexpression in the
stroma in PTs.48 In an MMTV-Wnt1 mouse mammary
tumor model, regression of mammary tumors by Wnt
inhibitor Fzd8CRD was associated with an acute and strong
induction of IGF-binding protein IGFBP5, another member
of the IGF-binding protein family and an antagonist of IGF
signaling that mediates involution of the mammary gland in
females after offspring are weaned. The crosstalk of b-
catenin with the IGF signaling pathway is also evidenced by
a moderate to strong association between b-catenin nuclear
staining and IGF1 overexpression in the stroma of the PTs.
ANCILLARY STUDIES IN PT
Currently, the differentiation of the PTs from fibroadeno-
mas is primarily based on the architecture, stromal
cellularity, stromal cell nuclear pleomorphism, mitoses,
and Ki-67 proliferation index of the stromal cells. Misdiag-
nosis of these 2 entities may occur because of the
heterogeneity of PTs or some overlapping features between
the fibroepithelial neoplasms.20,49 On the other hand,
grading of the PTs can be more difficult in CNB because
of limited samples. Many investigators have studied
immunohistologic markers to compare their expression in
fibroadenoma and PT, and their association with tumor
grade for the latter. Most of these markers are related to one
of the many molecular mechanisms or signaling pathways
involved in tumorigenesis, progression, and metastasis
discussed above. Based on our knowledge, there is no
single ‘‘magic’’ marker thus far to distinguish PTs from
fibroadenomas, or to accurately diagnose benign, border-
line, and malignant PTs. However, a panel of biomarkers
32 Arch Pathol Lab Med—Vol 138, January 2014
has been investigated, and some of them may be useful in
daily surgical pathology practice.
Ki-67 and Cell Proliferation Markers
The nuclear protein Ki-67 is a cell proliferation marker
expressed only in cycling cells. As a result, quantitative
assessment of Ki-67 nuclear staining on tumor samples
provides a good estimate of the proliferation index of
individual tumors. Ki-67 index is defined as the percentage
of cells with positive nuclear stains by MIB-1 antibody,
which recognizes Ki-67 antigen in the nucleus. Consistent
with other studies, our unpublished data84 also showed that
Ki-67 index increased in borderline and especially in
malignant PTs (Figure 9). Ki-67 proliferation index has
been significantly correlated with disease-free and overall
survival rates.50 Evaluation of the proliferative activity of the
PTs by Ki-67 index is one of the current World Health
Organization criteria for grading of PTs. Apparently, Ki-67
index is currently a useful marker considered in the
diagnosis or classifications of fibroepithelial lesions, but a
practical problem that exists is that there is no well-
established threshold for Ki-67 index for categorizing
various grades of PTs. The other issue is how the percentage
of Ki-67 immunoreactivity in tumor cells is estimated by
quantitative or semiquantitative methods. Given its utility
and promise as a biomarker, a large multicenter study with
long-term clinical follow-up and using computer-based
image analysis systems to estimate the percentage of Ki-67–
positive cells may be greatly valuable. Other cell prolifera-
tion markers that have been used include DNA Topoisom-
erase IIa and anaphase-promoting complex 7, whose
expression has been shown to correlate well with Ki-67
expression.51,52
CD117 (c-kit)
CD117 is a transmembrane protein of the type III receptor
tyrosine kinase family. It is crucial in regulating cell survival,
proliferation, and differentiation. It is recognized as a proto-
oncogene with frequent activating mutations and/or over-
expression in several types of neoplasms, including gastro-
intestinal stromal tumors, seminomas, melanomas, and
hematopoietic malignancies. Although increased CD117
expression in PTs has also been reported in several
studies,53–55 there is no association between CD117 expres-
sion and tumor grade, and furthermore, KIT-activating
mutations have not been found in PTs in other studies.56–58
Platelet-derived growth factor receptor alpha (PDGFRA) is
also a cell membrane tyrosine kinase receptor of the
platelet-derived growth factor family, and activating muta-
tions of PDGFRA have been associated with gastrointestinal
stromal tumors and a variety of other cancers. However, no
overexpression or mutation of PDGFRA has been observed
in PTs so far. In one study, none of the 41 PTs of the breast
expressed CD117.59 Based on current data, the application of
CD117 in differentiating fibroadenoma from PT or in the
grading of the latter remains to be investigated.
p53
The prototype tumor suppressor p53 is essential for cell
cycle control, DNA damage repair, and apoptosis. Defective
p53 may lead to abnormal cell proliferation and decreased
cell death, resulting in tumorigenesis. It is therefore not a
surprise that deregulation of p53 protein is observed in
approximately 50% of all human tumors. Under normal
cellular conditions, p53 is rapidly degraded by the protea-
Fibroepithelial Tumors of the Breast—Yang et al
some in a process mediated by MDM2 and JUN kinase.
After cellular stresses, such as exposure to DNA-damaging
agents, the half-life of the p53 protein is significantly
increased, and p53 accumulates in the nucleus of affected
cells. In PTs, several studies have shown strong but variable
degrees of nuclear p53 staining in malignant PTs, and p53
positivity was associated with an increased Ki-67 in-
dex.54,60–63 No p53 nuclear staining was observed in benign
tumors or fibroadenomas. Immunohistochemistry for p53
may be helpful in the grading of PTs but not for the
differentiation of fibroadenomas from benign tumors, and
the sensitivity is variable.
CD10
Contradictory results for CD10 positivity have been
reported. One study by Zamecnik et al64 showed CD10 to
be frequently positive in both fibroadenoma and PT (60%
and 67%, respectively). Thus, the authors believed that this
antibody could not assist in the differential diagnosis
between fibroadenoma and PT. This finding is in contrast
with other studies in which researchers showed CD10 is
preferentially expressed in borderline and especially in
malignant PTs but not in fibroadenomas or benign PTs,
and its expression is associated with tumor grade.65–67
Moritani and colleagues68 showed that CD10 appears to
highlight the myoepithelial cells in many benign breast
lesions, including fibroadenomas and PTs. Based on these
data, CD10 immunohistochemistry seems to be helpful only
in differentiating benign from borderline or malignant PTs
but not from fibroadenomas.
Cytokeratins
Chia and colleagues69 investigated a larger cohort of PTs
using a wide panel of commonly used keratins, including
MNF116, 34bE12, CK7, CK14, Cam5.2, and AE1/3. Contrary
to other studies, they observed some expression of keratins
MNF116, 34bE12, CK7, CK14, AE1/3, and Cam5.2 in the
stromal cells of 11.9%, 22%, 28.4%, 1.8%, 8.3%, and 1.8% of
PTs, respectively.69 However, keratin positivity was focal and
patchy and was found in only 1% to 5% of stromal cells in
these cases, and the explanation for keratin expression is
uncertain. In an earlier study, Dunne et al70 applied a panel
of keratins (AE1/AE3, 34bE12, CK5 and CK14, Cam5.2, CK7
and CK19, and EMA), of which all were negative in the
stromal components of 26 PTs. There has been another
study by Auger et al71 showing the presence of stromal
keratin expression in malignant PT. Overall, the stromal
keratin positivity in PTs remains inconclusive, but given
some reported cross-reactivity between keratins and stromal
cells in malignant PT, differentiation from spindle cell
metaplastic carcinoma may be difficult on core needle
biopsies, where the entire lesion with its architecture is not
seen.
Beta-Catenin and E-Cadherin Figure 9. MIB-1 (Ki-67) nuclear immunoreactivity increases with
Many genes are involved in the Wnt–b-catenin signaling tumor grade of the phyllodes tumors (PTs): (A) benign PT with  1% of
pathway. The expression of 5 key markers from the Wnt stromal cells positive; (B) borderline PT with approximately 2% to 3%
of cells positive; and (C) malignant PT with .10% of stromal cells
pathway, including markers b-catenin, E-cadherin, Wnt1, showing Ki-67 immunoreactivity (immunoperoxidase stain, original
Wnt5a, and SFRP4, in the PTs was examined by Karim et magnifications 3200).
al.48 Results suggested that stromal nuclear b-catenin
increased from normal breast tissue to benign PTs to
borderline PTs, and then decreased in malignant PTs, involved in the initiation and progression of PTs. However,
although the expression in the latter was still greater than some degree of nuclear b-catenin staining was observed in
that in normal breast tissue and benign PTs. This finding the stroma of all 30 fibroadenomas reported by Sawyer et
suggests that nuclear stromal accumulation of b-catenin is al.32 Furthermore, mammary fibromatosis is also associated
Arch Pathol Lab Med—Vol 138, January 2014 Fibroepithelial Tumors of the Breast—Yang et al 33
Figure 10. IMP3 immunohistochemistry. IMP3 is not expressed in benign (data not shown) and borderline (A) phyllodes tumors (PTs) but is
preferentially expressed in malignant PT. B, Note the negative epithelial component of the tumor (immunoperoxidase stain, original magnifications
3200).
with nuclear localization of b-catenin and mutation in the b-
catenin gene.72 Therefore, b-catenin immunostaining has a
limited role in the differential diagnosis of spindle cell
lesions of the breast on core needle biopsies. For E-
cadherin—an adhesion molecule forming complexes with
catenins at epithelial cell-cell adherens junctions that is lost
during epithelial-to-mesenchymal transition—positive
membrane staining is only seen in the epithelial cells, not
the stromal cells. Interestingly, decreased E-cadherin
expression in the epithelial cell membrane is significantly
correlated with increased mean time to recurrence.48
IGFs
The expression of IGF-I and IGF-II in both PTs and
fibroadenomas was studied by Sawyer et al32 in 2003. Many
of these tumors showed widespread overexpression of IGF-I
and, to a lesser extent, IGF-II throughout the stroma in both
PTs and fibroadenomas. In particular, IGF-I was largely
found in the densely cellular stromal regions away from the
epithelium. In the normal tissue surrounding the tumors, a
very low level of IGF1 and IGF2 expression could be seen in
the stroma. No IGF1 or IGF2 expression was seen in the
normal or tumor epithelium. Although IGF1 and IGF2
overexpression may be important in the pathogenesis of
fibroepithelial neoplasms of the breast, these markers may
not be useful in differentiating fibroadenomas from PTs.
EGFR
Several groups have shown EGFR expression in PTs, as
well as its association with tumor progression.59,73 Tse et al73
investigated 453 PTs (296 benign, 98 borderline, and 59
malignant) for EGFR expression using immunohistochem-
istry and fluorescence in situ hybridization for gene
amplification. The results showed a correlation between
EGFR expression and tumor margin status, tumor grade,
stromal cellularity, mitotic activity, nuclear pleomorphism,
and stromal overgrowth. The overall positive rates for EGFR
were 16.2% (48 of 296), 30.6% (30 of 98), and 56% (33 of 59)
for benign, borderline, and malignant PTs, respectively.
Fluorescence in situ hybridization demonstrated EGFR gene
amplification in 8% of EGFR-positive cases by immunohis-
tochemistry. In another study by Kersting et al,74 EGFR
34 Arch Pathol Lab Med—Vol 138, January 2014
positivity was detected in 19% of PTs (75% of all malignant
tumors) in stromal tumor cells but not in the epithelial
component, and it was correlated with p53 expression. Like
many other biomarkers, the overall low sensitivity can limit
its application in daily practice.
IMP3
IMP3 has been implicated recently as a novel biomarker in
many cancers, including lung,75 renal,76 pancreatic,77 cervical
adenocarcinoma,40 thyroid,78 and malignant mesothelio-
mas.79 In a series of 138 breast cancer cases, our recent study
showed that IMP3 expression was seen in 45 cases (33%),
and 25 of the IMP3-positive cases were triple-negative
breast carcinomas.43 There was a significant correlation
between IMP3 expression and higher grade (P ¼ .001),
necrosis (P , .001), and triple negativity and CK5/6
expression (P , .001 for each). Cox multivariate analysis
showed a hazard ratio of IMP3 expression at 3.14 (P ¼ .05).
IMP3 is a novel biomarker for triple-negative (basal like)
invasive mammary carcinoma, and its expression is associ-
ated with a more aggressive phenotype and decreased
overall survival. In a study by another group, membranous
positivity of IMP3 was reported in 81.3% of primary adenoid
cystic carcinomas of breast, a variant of triple-negative
breast cancers.80,81 In PTs of the breast, our unpublished
data84 showed that IMP3 is preferentially expressed in all
malignant PTs but not in borderline or benign tumors or
benign surrounding breast tissues (Figure 10), suggesting
IMP3 may serve as a good biomarker to identify malignant
PTs, especially in limited materials.
Chromosomal Changes
In a study by Lae et al,81 results showed that 83% of the
PTs had chromosomal imbalance, which segregated into 2
groups. Benign PTs showed one or a few chromosomal
changes, compared with numerous chromosomal imbal-
ances in borderline and malignant PTs. Among these
changes, gain of chromosome 1q and loss of 13q are the
hallmark alterations in PTs. Our understanding of these
chromosomal or genetic changes in the fibroepithelial
lesions needs to be further investigated. Huang et al82
studied the methylation profile of 11 genes in 86 PTs (15
Fibroepithelial Tumors of the Breast—Yang et al
benign, 28 borderline, and 43 malignant) and 26 fibroad-
enomas. They showed that significant levels of methylation
of 2 genes, including RASSF1A (24.4%) and TWIST1 (7.1%),
were observed in some PTs but absent in fibroadenomas,
suggesting that assessment of methylation of RASSF1A and
TWIST1 may aid in the diagnosis of PTs. Kim et al83 studied
promoter methylation of several genes and found there was
a higher methylation status in borderline and malignant PTs
than in benign tumors, although no significant difference
was found between the borderline and malignant tumors.
However, the specificity has not been addressed, and it
remains unclear whether fibroadenomas also have methyl-
ation changes. Currently the variable sensitivity of methyl-
ation of these genes makes this method impractical.
CONCLUSIONS
In summary, fibroepithelial tumors of the breast are a
heterogeneous group of biphasic lesions, with fibroadeno-
ma and PT being the 2 main prototypes. Phyllodes tumor is
further classified into benign, borderline, and malignant
categories. Because of some overlapping histologic features,
differentiation of fibroadenoma and benign PT, as well as
accurate grading of PT, may be difficult on a small core
needle biopsy. Because of significant differences in their
clinical behavior, complete excision of such indeterminate
lesions on needle biopsies may be needed, along with
appropriate clinical correlation for definitive classification of
fibroepithelial tumors. Some immunohistochemical mark-
ers, such as Ki-67 and IMP3, have shown promise to aid in
this differential diagnosis, especially for differentiating
borderline and malignant PTs, but as of now there is no
‘‘magic marker’’ with high sensitivity and specificity, and
morphology on a completely resected tumor remains the
gold standard. Large-scale or multi-institutional studies
with long follow-up may be needed to address these issues
in the future.
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Prepare Now for the CAP ’14 Abstract Program
Don’t Wait! Plan now to submit abstracts and case studies for the College of American
Pathologists (CAP) 2014 meeting, which will be held September 7th through the 10th in
Chicago, Ill. Submissions for the CAP ’14 Abstract Program will be accepted from:
Monday, January 13, 2014 through Friday, March 14, 2014
Accepted submissions will appear online on the Archives of Pathology & Laboratory
Medicine Web site. Visit the CAP ’14 website at http://www.cap.org/cap14 for additional
abstract program information as it becomes available.
36 Arch Pathol Lab Med—Vol 138, January 2014
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