Seminars in Diagnostic Pathology 34 (2017) 438–452

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Seminars in Diagnostic Pathology

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Fibroepithelial lesions; The WHO spectrum

Gregor Krings n, Gregory R. Bean, Yunn-Yi Chen
Department of Pathology, University of California San Francisco (UCSF), San Francisco, CA, USA

ar t ic l e i nf o a b s t r a c t

Fibroepithelial lesions of the breast comprise a morphologically and biologically heterogeneous group of
Keywords: biphasic tumors with epithelial and stromal components that demonstrate widely variable clinical be-
Phyllodes havior. Fibroadenomas are common benign tumors with a number of histologic variants, most of which
Fibroepithelial pose no diagnostic challenge. Cellular and juvenile fibroadenomas can have overlapping features with
Fibroadenoma phyllodes tumors and should be recognized. Phyllodes tumors constitute a spectrum of lesions with
Sarcoma varying clinical behavior and are graded as benign, borderline or malignant based on a set of histologic
Breast features according to recommendations by the World Health Organization (WHO). Recent developments
have significantly expanded our understanding of the pathogenesis of fibroepithelial lesions, highlighting
fibroadenomas as true neoplasms and underscoring a commonality with phyllodes tumors in the form of
recurrent MED12 exon 2 mutations. In addition, sequencing studies have elucidated pathways associated
with phyllodes tumor progression. Accurate diagnosis and grading of phyllodes tumors are important for
patient management and prognosis, as grade broadly correlates with increasing local recurrence risk, and
essentially only malignant tumors metastasize. However, classification of fibroepithelial lesions in many
cases remains challenging on both core biopsy and excision specimens. A commonly encountered pro-
blem at the benign end of the spectrum is the distinction of benign phyllodes tumor from cellular fi-
broadenoma, which is largely due to the subjective nature of histologic features used in diagnosis and
histologic overlap between lesions. Grading is further complicated by the requirement to integrate
multiple subjective and ill-defined parameters. On the opposite end of the histologic spectrum, malig-
nant phyllodes tumors must be distinguished from more common metaplastic carcinomas and from
primary or metastatic sarcomas, which can be especially difficult in core biopsies. Im-
munohistochemistry can be useful in the differential diagnosis but should be interpreted with attention
to caveats. This review provides an overview and update on the spectrum of fibroepithelial lesions, with
special emphasis on common problems and practical issues in diagnosis.
& 2017 Elsevier Inc. All rights reserved.

Introduction fibroadenomas and a commonality with phyllodes tumors in the

Fibroepithelial lesions of the breast constitute a heterogeneous
group of biphasic tumors with stromal and epithelial components
that demonstrate wide ranging biologic behavior and differences in
clinical management. These include common benign fibroadenomas
and fibroadenoma variants, as well as the spectrum of rare phyllodes
tumors, ranging from benign tumors with variable recurrence po-
tential to frankly malignant tumors with risk of metastasis and
death.1 Periductal stromal tumors likely represent phyllodes tumor
variants with periductal growth and are also included in this review.
Although the pathogenesis of fibroepithelial lesions remains poorly
understood overall, recent genomic studies have begun to uncover
the molecular underpinnings of fibroadenomas and phyllodes
tumors.2–7 These studies provide support for a clonal origin of
form of recurrent MED12 mutations, and also highlight the hetero-
geneity and molecular progression of phyllodes tumors.
Whereas the diagnosis of usual type fibroadenomas is typically
straightforward, accurate diagnosis of phyllodes tumors can be
challenging in many cases. Commonly encountered problems in-
clude phyllodes tumor grading and distinction of cellular fi-
broadenomas from the lower end of the histologic spectrum of
phyllodes tumors. The diagnostic difficulty arises in large part due
to overlapping histologic features and the subjective nature of the
assessed histologic parameters. In addition, phyllodes tumor
grading is further complicated by the need to evaluate and in-
tegrate multiple parameters whose relative weighted importance
can be observer dependent in the absence of clearly defined cri-
teria. Nonetheless, accurate diagnosis is important to help predict

n
Correspondence to: Department of Pathology, University of California San Francisco, 1825 4th Street, Room M-2355, San Francisco, CA 94143, USA.
E-mail address: gregor.krings@ucsf.edu (G. Krings).

http://dx.doi.org/10.1053/j.semdp.2017.05.006
0740-2570/& 2017 Elsevier Inc. All rights reserved.
 G. Krings et al. / Seminars in Diagnostic Pathology 34 (2017) 438–452
recurrence potential and guide clinical management. On the ma-
lignant end of the spectrum, distinction of malignant phyllodes
tumors from metaplastic carcinoma or sarcoma can be challenging
on core biopsy and excision, in which generous sampling and
immunohistochemistry can be useful to reach the correct diag-
nosis. Here, we provide a review on fibroepithelial lesions, in-
cluding recent advances in molecular pathogenesis, and with an
emphasis on problems and practical issues in diagnosis.
Fibroadenomas
Fibroadenomas are the most common fibroepithelial lesions
and most common benign tumors of the breast. The incidence is
highest in women less than 30 years old, but these tumors are not
uncommon in older age groups.1,8,9 Fibroadenomas are often small
(o 3 cm) but may be large and even rapidly growing, especially
juvenile fibroadenomas, which can raise clinical concern for
phyllodes tumor.1,10–12 An increased prevalence in younger wo-
men, tendency to regress or hyalinize with age, increased risk of
development with estrogen replacement therapy, and an associa-
tion with gynecomastia or hormonal imbalance in men all suggest
a role for hormonal influence in fibroadenoma development and
growth.10,13–17 Cyclosporine use in organ transplant patients has
been associated with multiple and/or bilateral fibroadenomas.18–20
Genetic risk factors remain unknown, but multiple and/or bilateral
fibroadenomas have been associated with a family history, and
Carney complex patients may develop multiple or bilateral myxoid
fibroadenomas.21,22
Fibroadenomas are well-circumscribed epithelial and stromal
proliferations derived from the terminal duct lobular unit (Fig. 1A).
Growth may be intracanalicular or pericanalicular, and both pat-
terns often coexist (Fig. 1B-C). In usual type fibroadenomas, stro-
mal cellularity is similar to that of normal perilobular stroma, and
there is no stromal atypia and no or only very widely scattered
mitotic activity. The stroma may be fibrous, myxoid (Fig. 1D),
hyalinized (Fig. 1E), or mixed. Benign heterologous stroma is rare
but most often lipomatous, with myoid, cartilaginous or osseous
metaplasia being exceedingly rare. Fibroadenomas with sclerosing
adenosis, papillary apocrine metaplasia, cysts or epithelial calcifi-
cations have been called complex fibroadenomas (Fig. 1F) and may
be associated with slightly higher risk of subsequent carcinoma
development, but this term is not recommended in routine
practice.23–25 Tubular adenomas are characterized by adenosis-like
proliferations of closely packed ductules with small lumina that
may have scant secretions (Fig. 1G); identification of MED12 mu-
tations in these lesions supports their classification as fi-
broadenoma variants with epithelial overgrowth 26, although
others have found no such association.27 Some fibroadenoma
variants demonstrate a more lobular rather than ductal archi-
tecture, and this is more common in juvenile fibroadenomas.28
Cellular fibroadenomas are defined by mild to moderately in-
creased stromal cellularity, although this feature is subjective and
lacking a diagnostic threshold (Fig. 2A–C). Juvenile fibroadenomas
are cellular fibroadenomas additionally characterized by perica-
nalicular growth and epithelial “gynecomastoid”/micropapillary
usual ductal hyperplasia (Fig. 2D–F). Juvenile fibroadenomas are
more common in adolescents and young women, but prevalence is
bimodal, with a second peak in women 4 40 years old.11,28–30
Stromal mitoses may be increased in cellular fibroadenomas, with
some suggesting an upper threshold of 2 mitotic figures/10 high
power fields (HPF).28,30–33 Although still averaging o2 mitotic
figures per 10 HPF in most cases, a subset of usual type and ju-
venile fibroadenomas in adolescents may be more mitotically ac-
tive (up to 6 and 7 mitoses/10 HPF, respectively), which is not
diagnostic of phyllodes tumor in the absence of other histologic
439
features.28,30 On the other hand, a diagnosis of phyllodes tumor
should be carefully considered in mitotically active cellular fi-
broepithelial lesions presenting in women significantly past ado-
lescence. Pediatric fibroadenomas may also demonstrate ill-de-
fined borders and often have small leaf-like fronds, although the
latter should not be diffuse or well-developed for this diagnosis.
While mitotic activity 4 2/10 HPF correlated with recurrence in
one recent study on pediatric fibroepithelial lesions, stromal cel-
lularity, border irregularity and frond-like growth in the absence
of other features of phyllodes tumor did not.30
Practical problems and challenges in diagnosis
The most challenging differential diagnosis is between cellular
fibroadenoma and phyllodes tumor, which is due to overlapping
and subjective histologic features and ill-defined criteria, as well
as tumor heterogeneity and sampling issues in core biopsies; this
is discussed in more detail below. In contrast, the diagnosis of a
usual type fibroadenoma is often facile if typical features are
present. Indeed, a diagnosis of fibroadenoma can be confidently
made on core biopsy if the lesion lacks stromal fronds, stromal
hypercellularity, atypia or mitotic activity. In this context, the al-
ternate diagnosis of phyllodes tumor on excision is o1% despite
the heterogeneity of many phyllodes tumors.34,35 Some fi-
broadenomas may show focal leaf-like architecture; if focal and
lacking hypercellular stroma, this should not be misinterpreted as
evidence for phyllodes tumor. Benign lipomatous metaplasia may
raise concern for infiltrative growth, especially on biopsy; low
stromal cellularity and lesional circumscription is often the clue to
the correct diagnosis in this context (see Fig. 6F). Fibroadenomas
with lipomatous metaplasia may also mimic hamartomas, but this
distinction is not clinically relevant. In limited and hypocellular
biopsy material, myxoid fibroadenomas may resemble mucinous
carcinomas (Fig. 3A–B), which are also radiologically similar.36
Mucin of mucinous carcinomas is often more fibrillary and blue-
tinged than the homogenous white-tan stroma of myxoid fi-
broadenomas. Level sections or immunohistochemistry for
myoepithelial cells may be helpful in challenging cases. Un-
commonly, the stroma of higher grade phyllodes tumors can also
be paradoxically hypocellular and myxoid-appearing. Rarely, fi-
broadenomas with cyst-like spaces from stromal retraction can
mimic intraductal papillomas, and vice versa (Fig. 3C–D). On core
biopsy, sclerosing adenosis, cysts, apocrine change or epithelial
proliferation may mask an underlying fibroepithelial lesion
(Fig. 3E), and sclerosing lesions with fibroglandular distortion and
altered stroma may conversely mimic complex fibroadenoma.
Tubular adenomas may resemble ductal adenomas or intraductal
papillomas with adenosis; the ductules of tubular adenomas are
round to oval, in contrast to the irregular jagged ductules em-
bedded in hyalinized stroma of sclerosed papillomas/ductal ade-
nomas. Fibroadenomas can rarely infarct sporadically or during
pregnancy, lactation or following biopsy procedures, which should
not necessarily be misinterpreted as a worrisome feature
(Fig. 3F).37–40
Pathogenesis and molecular pathology
The pathogenesis of fibroadenomas overall remains poorly
understood, but epithelial-stromal interactions are thought to be
central to their development and to the development and growth
of fibroepithelial lesions in general. Sawyer et al. postulated a role
for stromal insulin-like growth factor (IGF) 1 and IGF-2 signaling
through β-catenin.41 Along with epidemiologic and clin-
icopathologic evidence, a role for hormonal influence is supported
by stromal ERβ expression and recurrent somatic mutations in
MED12, a component of the multiprotein transcriptional regulator
440 G. Krings et al. / Seminars in Diagnostic Pathology 34 (2017) 438–452

Fig. 1. Fibroadenoma and Fibroadenoma Variants. (A) Fibroadenomas are well-circumscribed biphasic tumors with epithelial and stromal components. (B) Intracanalicular
growth pattern, with compression of ducts into elongated curvilinear structures (C) Pericanalicular growth pattern, with circumferential stromal proliferation around non-
compressed ducts with open lumina. (D) Myxoid fibroadenoma (E) Hyalinized fibroadenoma, with dense sclerotic stroma and associated calcifications (F) Complex fi-
broadenoma, in this case showing epithelial cysts and foci of sclerosing adenosis. (G) Tubular adenomas are characterized by adenosis-like proliferations of closely-packed
ductules, often with luminal secretions (inset). (H) Lactational change may be seen during pregnancy or lactation.
 G. Krings et al. / Seminars in Diagnostic Pathology 34 (2017) 438–452 441

Fig. 2. Cellular and Juvenile Fibroadenomas. (A-C) Cellular fibroadenoma (A, B) Well-circumscribed cellular fibroepithelial lesion with uniform distribution of epithelium and
stroma (C) High power magnification shows mild to moderately cellular stroma without significant nuclear atypia. (D–F) Juvenile fibroadenoma (D) Peripheral circum-
scription, pericanalicular growth pattern, uniformly distributed epithelium, and mildly proliferative epithelium are evident on low power evaluation. High power view
reveals (E) mild stromal cellularity without atypia and (F) characteristic gynecomastoid-type/micropapillary usual ductal hyperplasia of epithelial component.

Mediator complex that shows a similar spectrum of mutations in
uterine leiomyomas.2,10,13–17,26,42–47 Mutations in exon 2 of MED12
have been identified across the spectrum of breast fibroepithelial
lesions, including up to 65% of fibroadenomas, with the vast ma-
jority of these occurring at codon 44.2,26,45,46 MED12 mutations
were shown to be confined to the microdissected stromal
component,2 and mutation status correlates with stromal but not
epithelial MED12 protein expression.47 MED12 mutations do not
clearly correlate with stromal or epithelial ERα/ERβ expression,
indicating that the proposed functional impact on ER signaling
requires additional study.47 MED12 mutations may be more fre-
quently associated with intracanalicular growth.45,48 Mutations
clustering in the ligand-binding domain of the retinoic acid
receptor α (RARA) gene have also been identified in fibroadenomas
and phyllodes tumors and were shown to impact RARA-mediated
transcription.3 The identification of recurrent stromal MED12 and
RARA mutations is indicative of monoclonality and supports the
classification of at least some fibroadenomas as neoplastic rather
than hyperplastic lesions. This is in contrast to some earlier studies
that used comparative genomic hybridization and polymerase
chain reaction (PCR)-based approaches to suggest a polyclonal
stromal origin.49–52 The apparent discrepancy can likely be ex-
plained at least in part by low lesional stromal cellularity that can
mask clonality in the latter assays. Indeed, fibroadenomas with
more cellular stroma or “phyllodal features” were shown to be
clonal using these techniques.51–53 Interestingly, a recent study
442 G. Krings et al. / Seminars in Diagnostic Pathology 34 (2017) 438–452

Fig. 3. Histologic Mimics of Fibroadenoma. (A) Myxoid fibroadenoma and (B) mucinous carcinoma may sometimes mimic each other, especially in scant core biopsy spe-
cimens. (C) Gaping ducts in fibroadenoma with stromal retraction can sometimes mimic intraductal papilloma if the intracanalicular growth pattern is not recognized (inset),
especially in core biopsies. (D) Conversely, fragmentation of a biopsied intraductal papilloma may sometimes mimic features of a fibroepithelial lesion. (E) Sclerosing
adenosis, variably dilated cysts and stromal fibrosis of complex fibroadenomas can mimic a sclerosing lesion on core biopsy. The presence of elongated curvilinear ducts
(bottom left) can be a clue to the correct diagnosis. (F) Necrosis (shown here in a core biopsy of fibroadenoma) can be seen in fibroepithelial lesions due to infarction during
pregnancy or lactation, following a prior procedure, or spontaneously, and is not necessarily worrisome in the absence of other features of phyllodes tumor.

found that myxoid fibroadenomas did not harbor MED12 muta-
tions. Although limited in number of cases, this report potentially
suggests an alternate pathogenesis for these variants.54
Phyllodes tumors
Phyllodes tumors are rare, comprising 2.5% of fibroepithelial
lesions and 0.3–1% of all primary breast tumors.1,31 These tumors
have inherent recurrence and/or metastatic potential, which varies
based on histologic grade.1 The majority of tumors (60–75%) are
benign, with borderline and malignant tumors constituting 15–20%
and 10–20%, respectively.1,55,56 Phyllodes tumors often present as a
rapidly growing mass or accelerated growth of a previously stable
lesion, and growth rate may be demonstrably faster than fi-
broadenomas by ultrasound.57 However, phyllodes tumors cannot
be reliably distinguished from fibroadenomas by imaging.58–61
Average tumor size is 4–5 cm, but size ranges widely from sub-
centimeter to 430 cm.55,62–68 Large tumors may cause skin dis-
coloration, thinning, or ulceration.1,64,67 Although axillary lympha-
denopathy is common, nodal metastases are very rare.69 Age at
presentation (40–50 years) is on average 10–20 years older than
fibroadenomas, but these tumors can present at any
age.1,28,30,63,64,70,71 Phyllodes tumors are more common and may
 G. Krings et al. / Seminars in Diagnostic Pathology 34 (2017) 438–452 443

present at earlier age in Asian and Latina women.1,72 Rare reports in
men are often associated with gynecomastia, suggesting a role for
hormonal imbalance.73–75 Genetic risk factors are largely unknown,
but phyllodes tumors have been described in Li-Fraumeni syn-
drome patients and in a mother and daughter pair.76–78
Phyllodes tumors are hypercellular fibroepithelial tumors and
characteristically demonstrate an exaggerated intracanalicular
growth pattern with leaf-like stromal proliferations protruding
into dilated clefts or gaping cyst-like spaces (Fig. 4A–B). Some
cases demonstrate periductal or subepithelial stromal condensa-
tion, with increased stromal cell density subjacent to the
epithelium (Fig. 4C).1 Mitotic activity may be increased in this
zone. The stroma is usually fibrous, myxoid, or hyalinized and not
infrequently shows heterogeneity in terms of cellularity, matrix
type and epithelial density. Pseudoangiomatous stromal hyper-
plasia (PASH) may be seen. Mature stromal metaplasia is rare but if
present is often lipomatous.79
Phyllodes tumors are graded according to recommendations by
the World Health Organization (WHO) as benign, borderline, or
malignant based on the presence and degree of stromal cellularity,
atypia, mitotic activity, border infiltration versus circumscription
and stromal overgrowth (Table 1).1 Stromal overgrowth is defined

Fig. 4. Histologic Features of Phyllodes Tumors. (A–B) Benign phyllodes tumor showing (A) well-circumscribed borders without infiltrative growth and with characteristic leaf-
like architecture (B) High power magnification reveals mild cellularity of the stromal fronds with no to mild stromal cell cytologic atypia. Mitotic activity was scant
(averaging 1 mitosis/10 HPF; not shown). (C) Stromal condensation, with increased stromal cellularity subjacent to the epithelium; mitotic activity may be identified in this
zone. Stromal condensation can be subjective to evaluate but supports a diagnosis of phyllodes tumor. (D–E and F) Borderline phyllodes tumors (D) This tumor demonstrates
well-developed leaf-like growth (inset) and circumscribed borders (not shown), in most areas showing mild to moderate stromal cellularity, mild stromal cell atypia and few
mitoses. A more cellular area with (E) moderate cytologic atypia and increased mitoses (up to 9/10 HPF) was identified, most consistent with borderline phyllodes tumor.
(F) Infiltrative growth and stromal overgrowth, even if focal, are generally features of at least borderline tumors.
444 G. Krings et al. / Seminars in Diagnostic Pathology 34 (2017) 438–452

as proliferative stroma resulting in lack of epithelium in at least one periductal stromal sarcoma was defined as having moderate
low-power (4x objective, 10x ocular) microscopic field. Grading stromal atypia, at least 3 mitotic figures/10 HPF, and infiltrative
requires evaluation of the entire lesion and should be based on an growth, whereas periductal stromal hyperplasia was non-in-
excision specimen.80,81 Benign phyllodes tumors are mildly cellular filtrative with less atypia and mitoses. However, this classification
without stromal overgrowth, have only mild atypia with o5 mi- does not clearly correlate with recurrence, and the term periductal
totic figures/10 HPF, and have well-circumscribed, pushing borders stromal tumor is preferred over sarcoma.86 Recurrences often re-
without infiltrative growth (Fig. 4A–B). On the other end of the semble phyllodes tumors.
spectrum, malignant tumors show marked stromal cellularity,
marked atypia, numerous mitoses (Z10 mitotic figures/10 HPF) Practical problems and challenges in diagnosis
and at least focal stromal overgrowth with infiltrative borders
(Fig. 5A–C). Malignant heterologous stroma defines malignancy Phyllodes tumor grading
regardless of the presence of the other features. Liposarcomatous Phyllodes tumor grade correlates with risk of recurrence and
differentiation is most common, but chondrosarcoma, osteosarco- metastasis and is important for patient management, but grading
ma, rhabdomyosarcoma and others may rarely be seen, sometimes can be challenging in practice. This is highlighted in a study by
in combination (Fig. 5D–F).1,63 Borderline tumors show some but Lawton et al., in which individual diagnoses ranged from fi-
not all features of malignancy, often with an intermediate mitotic broadenoma to borderline phyllodes tumor in 9 (43%) of 21 chal-
count, and accordingly may be varied in appearance (Fig. 4D–F). lenging cellular fibroepithelial lesions reviewed by ten breast pa-
Numerous studies have evaluated immunohistochemical markers thologists. The grade of one phyllodes tumor in this study ranged
as adjuncts for grading and tumor behavior; although many (in- from benign to malignant.87 Of the criteria determining grade,
cluding p53, CD117, EGFR, VEGF, CD10 and Ki67) correlate with stromal cellularity and atypia in particular are each inherently
grade, none has been shown to independently predict recurrence or subjective and may be heterogeneous throughout the tumor. In-
metastasis.82 terpretative differences are expected to be greatest in lesions
Although histologic grading estimates the risk of phyllodes bordering between mild and moderate or between moderate and
tumor recurrence and/or metastasis, grading is not necessarily marked categories. A reasonable approach is to define mild hy-
predictive of tumor aggression in individual cases.1,63 Nonetheless, percellularity as increased in comparison to normal perilobular
grade has been shown to correlate with behavior, with malignant stroma but with well-spaced nuclei showing no overlap, whereas
phyllodes tumors showing the highest risk for local recurrence (up the nuclei of markedly hypercellular stroma show confluent areas
to 23–30%) and also demonstrating metastatic potential (up to 22% of dense nuclear overlap; moderate cellularity is intermediate
of cases).1,63 Borderline tumors may have very low (0–4%) meta- between the two extremes.32,88 Mild atypia is characterized by
static potential, whereas benign tumors are generally not thought small, uniform nuclei with smooth borders, not much different
to metastasize. Rare benign tumors preceding metastasis have from normal perilobular stroma, and marked atypia is defined by
been reported, but inadequate sampling of higher grade areas of marked nuclear pleomorphism with coarse chromatin, irregular
heterogeneous tumors cannot be excluded.83 Although local re- membranes and nucleoli; moderate atypia falls between the
currences are usually of the same grade as the primary tumor, two.32,88
tumors may occasionally recur with higher or lower grade than Intratumoral heterogeneity may further complicate the inter-
initial presentation, which may be due to progression and/or in- pretation, and good practice may be to evaluate atypia, cellularity
tratumoral heterogeneity.63,67,71,84 Metastases are essentially al- and mitotic activity in the most affected area of the tumor, which
ways composed of the stromal component and are most com- should be adequately sampled to include at least 1 section per cm
monly of spindle cell morphology.85 Heterologous sarcomatous of gross tumor size, as well as grossly heterogenous areas. In ad-
elements in the primary tumor may or may not be present in the dition to subjectivity of individual criteria, grading requires in-
metastasis, and the metastasis rarely demonstrates heterologous tegration of the multiple parameters, which can be further con-
stroma not present in the primary tumor. founding. A particular problem in this regard is the determination
Periductal stromal tumors are considered phyllodes tumor of malignancy, which is a critical distinction given the high risk for
variants characterized by periductal stromal proliferation asso- metastatic disease and poor outcome. Indeed, in one study, all
ciated with non-compressed or dilated ducts. Adjacent pro- phyllodes tumor metastases and deaths were preceded by a ma-
liferative nodules can coalesce to form a larger mass. Initially, lignant primary diagnosis.68 Despite these prognostic implications,
the histologic threshold required for a malignant diagnosis re-
Table 1 mains poorly defined. From a practical standpoint, we require the
Histologic features of phyllodes tumorsa. presence of all five main malignant features (marked stromal
cellularity, Z 10 stromal mitoses/10 HPF, marked stromal atypia,
Benign Borderline Malignant
stromal overgrowth and infiltrative tumor borders) or the pre-
Stromal Mild, non-uni- Moderate, non- Marked, sence of malignant heterologous stromal differentiation for a di-
hypercellularity form or diffuse uniform or diffuse usually agnosis of malignant phyllodes tumor.1,88 Occasional tumors have
diffuse only focal marked cellularity, atypia and elevated mitotic rate, with
Stromal mitotic 0–4/10 HPF 5–9/10 HPF Z 10/10 HPF
activity
the rest of the tumor resembling lower grade phyllodes tumor
Stromal cell atypia Mild or none Mild or moderate Marked (Fig. 4D–E). We recommend classification of such tumors as bor-
Stromal overgrowth Absent May be focal Usually pre- derline, with an acknowledgment of possible metastatic potential.
sent, may be
diffuse
Differential diagnosis of benign cellular fibroepithelial lesions
Tumor borders Circumscribed, Circumscribed or Infiltrative
pushing focally infiltrative Distinction of cellular fibroadenoma from benign phyllodes tu-
Malignant hetero- Absent Absent Presentb mor is a common diagnostic challenge (Table 2). This was further
logous highlighted in the interobserver study by Lawton et al., in which
differentiation agreement among all pathologists was seen in only 2 (9.5%) of the
Adapted from.1
a 21 challenging fibroepithelial lesions.87 The diagnosis of phyllodes
b
Malignant heterologous differentiation defines malignancy even in the tumor is usually not problematic in the presence of a cellular fi-
absence of the other features. broepithelial tumor with classic well-developed leaf-like
 G. Krings et al. / Seminars in Diagnostic Pathology 34 (2017) 438–452 445

Fig. 5. Malignant Phyllodes Tumor. (A) Markedly hypercellular stroma is evident at low power of this malignant phyllodes tumor, which retains areas of well-developed leaf-
like growth. (B) In other cases, the epithelial component is scant due to marked stromal overgrowth, and extensive tumor sampling may be required. Note also the markedly
infiltrative tumor border. (C) High power magnification reveals markedly cellular stroma and marked cytologic atypia with pleomorphic nuclei and abundant mitotic activity
( Z 10 mitoses/10 HPF). All histologic criteria should generally be present for a diagnosis of malignant phyllodes tumor, although (D–F) malignant heterologous stroma itself
is sufficient for a malignant diagnosis. (D) Liposarcomatous differentiation is the most common type of malignant heterologous differentiation. (E) Mixed osteosarcomatous
and chondrosarcomatous differentiation in malignant phyllodes tumor. Note background fibroepithelial architecture in D and E insets. (F) Leiomyosarcomatous differ-
entiation in malignant phyllodes tumor, supported by desmin expression by the malignant smooth muscle tumor cells (inset).

architecture. The difficulty in other cases stems from the application
of subjective criteria (stromal cellularity, atypia, well-developed
leaf-like growth, stromal condensation) with overlapping features
between groups. Whereas fibroadenomas classically lack stromal
cell atypia, this feature can be subjective, especially at the mild end
of the spectrum as would be typical of benign phyllodes tumor.
Cellularity and mitotic activity of benign phyllodes tumor (0–4
mitoses/10 HPF) overlap with cellular and juvenile fibroadenomas
in adults and children.28,30,32 Leaf-like growth is the best dis-
criminator between the two groups but is not always prominent or
well-developed in phyllodes tumors, and lack thereof should not
exclude the diagnosis when a cellular fibroepithelial lesion shows
other features of phyllodes tumor, such as clear cut stromal atypia,
overgrowth, and/or infiltrative borders. On the other hand, leaf-like
areas may be seen in some fibroadenomas (Fig. 6C), but these are
characteristically focal and less cellular without stromal condensa-
tion. The fronds of such fibroadenomas appear to fit together like a
jigsaw puzzle, as opposed to phyllodes tumor, in which the bulbous
stroma protrudes into gaping cyst-like spaces. Focal leaf-like growth
may be especially common in pediatric fibroepithelial lesions and
should be interpreted with caution in the absence of other phyllodal
features.30
446 G. Krings et al. / Seminars in Diagnostic Pathology 34 (2017) 438–452
Table 2
Morphologic features of benign phyllodes tumor versus cellular fibroadenoma.
Benign phyllodes Cellular
tumor Fibroadenoma
Leaf-like growth pattern Present, well- Absent or focal
developed
Periductal stromal condensation May be present Absent
Stromal heterogeneity May be present Usually absent
Stromal cell atypia Mild Nonea
Stromal hypercellularity Mild Mild
Stromal mitoses 0–4/10 HPF Fewb
Pseudoangiomatous stromal May be present Rarely present
hyperplasia
Squamous metaplasia May be present Virtually absent
a
Multinucleated stromal giant cells may be seen.
b
Typically r 2/10 HPF, but may be more numerous in children, adolescents
and young women.
Given the overlap between cellular fibroadenoma and benign
phyllodes tumor, stromal cellularity alone is usually not a useful
discriminator on the low end of the histologic spectrum; however,
cellular fibroadenomas lack significant nuclear overlap or sheet-
like stromal growth, which favor phyllodes tumor. In our experi-
ence, loose fascicular stromal growth can also favor phyllodes
tumor. Prominent stromal heterogeneity may also support phyl-
lodes tumor (Fig. 6G-H), as cellular fibroadenomas are typically
more uniform in epithelial-stromal distribution and character of
the stroma (Fig. 2). Anecdotally, we find squamous metaplasia of
the epithelial component to be more common in phyllodes tumors
(Fig. 6E), which may result from friction of the bulbous stromal
fronds with the duct walls.
Benign multinucleated giant cells may be encountered in fi-
broepithelial lesions, including both fibroadenomas and phyllodes
tumors, and may be a diagnostic pitfall. These cells are typically
present as discrete subpopulations with degenerative-type atypia,
which contrasts with the more dispersed distribution of neoplastic
stromal cells with irregular nuclear membranes, coarse chromatin,
and possible mitotic activity in phyllodes tumors.68,89
Some fibroepithelial lesions may simply not be histologically
distinguishable as cellular fibroadenomas or benign phyllodes tu-
mors. In such cases, a diagnosis of benign fibroepithelial neoplasm
can be rendered, with an explanation of the features present, the
difficulty in categorization, distance to margins, and some risk but
low likelihood of local recurrence.1,31
The distinction between cellular fibroadenoma and phyllodes
tumor is particularly problematic in core biopsies (Fig. 6A). Nu-
merous studies have attempted to identify histopathologic factors
in core biopsies that could predict phyllodes tumor on
excision.32–34,80,90,91 Not surprisingly, features reported to be use-
ful are variable between studies, which can be explained by the
inherently heterogeneous character of fibroepithelial lesions, the
subjectivity of histologic criteria and thresholds, and tissue sam-
pling. Stromal cellularity and/or proliferative indices (mitotic ac-
tivity, Ki67) have been described as the most promising
features.32–34,80,90 However, due to subjectivity of stromal cellu-
larity evaluation and overlap of proliferative indices between
groups, practical utility is likely limited to lesions at the more
extreme ends of the spectrum.32,90 PASH stroma in a fi-
broepithelial lesion may be a more objective feature to raise
concern for phyllodes tumor on core biopsy and can provide
support for excision and evaluation of the entire lesion (Fig. 6D).90
Consistent with the inter- and intra-lesional heterogeneity of fi-
broepithelial lesions, Yasir et al. concluded that a combination of
3 or more of 7 adverse features may be more predictive than in-
dividual features, with phyllodes tumors averaging more features
(3.9) than fibroadenomas (1.4). A combination of stromal
heterogeneity, subepithelial condensation, and stromal pleo-
morphism were considered most useful, although the subjective
nature of these features again questions their overall practical
utility.33 Tan et al. described a 5-gene RT-PCR signature that may
help predict phyllodes tumor on excision, but included fi-
broadenomas of the usual type, and validation with cellular fi-
broadenomas is needed.92 In summary, no feature(s) on core
biopsy can reliably predict phyllodes tumor over cellular fi-
broadenoma in lesions that are not obviously at the higher end of
the phyllodes tumor spectrum. A diagnosis of fibroepithelial lesion
with cellular stroma with recommendation for excision for more
complete characterization is most prudent in such cases.
Differential diagnosis of malignant phyllodes tumor
The differential diagnosis of malignant phyllodes tumors pri-
marily includes metaplastic carcinoma and primary or metastatic
sarcoma, which can be problematic on core biopsy and in excision
specimens (Table 3). Metaplastic carcinoma is more common than
malignant phyllodes tumor or breast sarcoma and should always be
excluded.1 Accurate diagnosis on core biopsy can have important
clinical implications, as neoadjuvant chemotherapy and sentinel
lymph node biopsy at time of surgery may be considered for me-
taplastic carcinoma but not phyllodes tumor.93 A recent study
suggested that malignant phyllodes tumors and breast sarcomas
have similar clinicopathologic features, outcomes and treatment,
and the relevance of this distinction is currently less clear.94
The presence of characteristic leaf-like growth facilitates the
diagnosis of malignant phyllodes tumor in straightforward cases
(Fig. 5A). Breast sarcomas usually displace rather than entrap
mammary epithelium. An associated malignant epithelial com-
ponent or in situ carcinoma favors metaplastic carcinoma, but
heterologous elements are not specific to any of the entities and
are not useful. Malignant phyllodes tumors with extensive stromal
overgrowth are more problematic and can mimic spindle cell or
other metaplastic carcinomas and sarcomas. Extensive sampling of
an excision specimen may be required to identify the associated
epithelial component of phyllodes tumor, which can be very focal.
The distinction may be especially difficult in core biopsies
(Fig. 7A), and immunohistochemistry can be useful. Metaplastic
carcinomas express p63 and cytokeratins, especially high-mole-
cular-weight keratins (such as 34βE12, CK5/6, CK14 and AE1/3),
but staining can vary between markers and may be focal.1,95–98
Importantly, phyllodes tumors can be focally (1–5%) cytokeratin
positive (Fig. 7B), which increases with grade and was only seen in
malignant tumors in one study.95,96,99,100 Similarly, malignant
phyllodes tumors may focally express p63 in up 57% of cases
(Fig. 7C).95 Accordingly, focal keratin or p63 positivity does not
exclude phyllodes tumor, especially on core biopsy, and a diag-
nosis of malignant neoplasm with spindle cell features may be
prudent. On the other hand, diffuse strong positive keratin or p63
staining favors metaplastic carcinoma. The TP63 splice variant p40
may be more specific (86% vs. 43%) but less sensitive (46% vs. 62%)
than p63 for metaplastic carcinoma over malignant phyllodes tu-
mors, but this is based on a small tissue microarray study and
requires further validation.95 CD34 is negative in metaplastic car-
cinomas, and expression decreases with increasing phyllodes tu-
mor grade, being negative in up to 43% of malignant tumors.101,102
Therefore, CD34 expression excludes metaplastic carcinoma
(Fig. 7E), but negative staining is not helpful. We recommend a
large panel of high- and low-molecular weight cytokeratins, p63
and CD34 to help establish the diagnosis. In one study, 66% of
metaplastic carcinomas but no phyllodes tumors (including 14
malignant tumors) expressed Sox10, and GATA3 may be more
frequently positive in metaplastic carcinomas, but these markers
require further study.103,104
 G. Krings et al. / Seminars in Diagnostic Pathology 34 (2017) 438–452 447

Fig. 6. Histologic Features of Cellular Fibroadenomas versus Benign Phyllodes Tumors. (A) Core biopsy of fibroepithelial lesion with cellular stroma. Distinction between cellular
fibroadenoma and phyllodes tumor is often not possible on core biopsy, and final classification can be deferred to an excision specimen. (B) Tissue fragmentation in core
biopsy specimens is not specific to phyllodes tumor and can also be seen in fibroadenomas with intracanalicular growth, as in this case (inset shows fibroadenoma in the
excision specimen of the biopsied lesion). (C) Focal leaf-like growth in a fibroadenoma. When present, this is generally focal, poorly-developed and less cellular, in contrast to
phyllodes tumors. (D) Pseudoangiomatous stromal hyperplasia in benign phyllodes tumor (see inset). On core biopsy, this feature in combination with others can raise
consideration for phyllodes tumor and advocate for excision. (E) Squamous metaplasia in benign phyllodes tumor (inset with high power magnification). (F) Lipomatous
metaplasia in a cellular fibroadenoma. Note the lack of leaf-like growth and overall lesional circumscription, with fat confined within the rounded lesional borders, in
contrast to infiltrative growth that can be seen in phyllodes tumors. (G, H) Heterogeneity in phyllodes tumors with fibroadenoma-like areas. (G) Benign phyllodes tumor with
area of distinct leaf-like growth and hypercellular stroma (top) adjacent to area with hypocellular hyalinized stroma that is otherwise indistiguishable form fibroadenoma
(bottom). (H) Phyllodes tumor with central area of stromal overgrowth and focal leaf-like architecture (bottom right), as well as other peripheral areas indistinguishable from
hyalinized fibroadenoma.
448 G. Krings et al. / Seminars in Diagnostic Pathology 34 (2017) 438–452

Table 3
Useful histopathologic features in the differential diagnosis of malignant spindle cell lesions of the breast.

Malignant phyllodes tumor Metaplastic spindle cell carcinoma Sarcoma (primary or metastatic)

Leaf-like growth pattern Often presenta Absent Absent

Heterologous differentiation May be present May be present Tumor lineage-dependent
Conventional invasive carcinoma Absent May be presentb Absent
Ductal carcinoma in situ Absentc May be present Absent
Cytokeratin(s)d Negative or focal Positive Negative or focal
p63 Negative or focal Positive Negative or focal
CD34 Positive or negativee Negative Positive or negative

a
May be focal or absent with extensive stromal overgrowth, especially on core biopsy.
b
Most often ductal, may be squamous.
c
May rarely be involved by ductal carcinoma in situ.
d
Panel of high- and low- molecular weight cytokeratins is recommended.
e
Decreases with increasing phyllodes tumor grade; often negative in malignant tumors.

Fig. 7. Immunohistochemistry in the Differential Diagnosis of High-Grade Spindle Cell Lesions of the Breast. (A) Core biopsy of a high-grade spindle cell neoplasm - The
differential diagnosis includes malignant phyllodes tumor, metaplastic (spindle cell) carcinoma and primary/metastatic sarcoma, which often cannot be distinguished on
core biopsy. Malignant phyllodes tumors may focally express (B) cytokeratin(s) and/or (C) p63, and focal staining for these markers does not exclude the diagnosis. On the
other hand, diffuse keratin and/or p63 expression can favor metaplastic carcinoma. (D) Excision specimen of tumor shown in B and C reveals residual leaf-like growth
characteristic of malignant phyllodes tumor with prominent stromal overgrowth. Extensive tumor sampling may be required to identify the epithelial component. CD34
expression decreases with increasing phyllodes tumor grade, and CD34 is immunopositive in only a subset of malignant phyllodes tumors. (E) Strong diffuse CD34 im-
munostaining excludes metaplastic carcinoma, but negative staining is not helpful. (F) Nuclear β-catenin expression can be seen in metaplastic carcinomas, malignant
phyllodes tumors (shown here), and other lesions (such as fibromatosis) and is not helpful in the differential diagnosis.
 G. Krings et al. / Seminars in Diagnostic Pathology 34 (2017) 438–452
Pathogenesis and molecular pathology
The stromal component of phyllodes tumors is neoplastic.49,52,105
Similar to fibroadenomas, epithelial-stromal interactions are con-
sidered to play a key role in tumor development. Supportive evi-
dence for this view includes morphologic observations of stromal
condensation and mitotic activity in the subepithelial zone, de-
creasing epithelial ER and PR expression with increasing tumor
grade, and correlation of epithelial Wnt5a expression with stromal β-
catenin activation.106–108 Some studies have also demonstrated
monoclonality of the epithelial component.52,109 It has been postu-
lated that the stroma becomes independent of epithelial interactions
with progression towards malignancy.107
A number of studies have attempted to characterize the mo-
lecular features of phyllodes tumors in order to understand their
pathogenesis and identify factors that may predict outcome. Col-
lectively, these have shown increased karyotypic complexity, more
chromosomal gains and losses, and increased loss of hetero-
zygosity (LOH) with increasing tumor grade.84,109–115 The presence
of spatial and temporal intratumoral heterogeneity with respect to
copy number changes, including in morphologically similar and
distinct areas, may in part explain the imperfect correlation be-
tween histologic grading and tumor behavior, with implications
for tumor recurrence and progression.6,84
More recent DNA sequencing studies have identified recurrent
MED12 exon 2 mutations in phyllodes tumors. The mutational
spectrum is similar to that of fibroadenomas, with enrichment of
mutations at codon 44, supporting an underlying commonality in
pathogenesis.3,4,26,45–48,105,116,117 All grades of phyllodes tumor
harbor MED12 mutations, with some but not all studies suggesting
a lower frequency in malignant tumors.45,46,48,105,117,118 Given a
postulated association of MED12 with estrogen signaling, this
suggests possible loss of hormonal dependence in malignant tu-
mors but requires further study. Interestingly, Ng et al. reported
longer disease-free survival in patients with MED12-mutated
compared to MED12 wild-type tumors on univariate analysis,
which was not identified with grade alone.116 Additional aberra-
tions in cancer-related genes are associated with tumor progres-
sion in borderline and malignant tumors. These include the tumor
suppressors TP53, RB1, NF1 and PTEN, oncogenes such as PIK3CA,
BRAF and EGFR, and chromatin remodeling genes SETD2 and
KMT2D/MLL2, among others.3–6 In one study, 80% of malignant
phyllodes tumors showed aberrations in phosphatidyl inositol-3
kinase or Ras signaling pathways.6 Telomerase reverse tran-
scriptase (TERT) hotspot promoter mutations or amplifications are
also associated with phyllodes tumor progression, being most
frequent in malignant tumors.4–6,119 Discrepant reports of TERT
promoter mutations in fibroadenomas and benign phyllodes tu-
mors may be due to differing diagnostic thresholds or sample
sizes.5,6,119 Tumors with malignant heterologous stroma show
evidence of divergent evolution between heterologous and non-
heterologous areas; interestingly, those with liposarcomatous
differentiation lack CDK4/MDM2 amplification characteristic of
well-differentiated soft tissue liposarcoma, suggesting an alternate
pathogenesis despite histologic similarity.6,120 Together, these
studies highlight pathways important for tumor progression and
may identify potentially actionable targets, especially in malignant
tumors without effective treatment strategies beyond surgery.
Given their morphologic similarities, it has long been suggested
that some phyllodes tumors may arise from fibroadenomas. Per-
haps the subset of heterogeneous phyllodes tumors with fi-
broadenoma-like areas may arise from fibroadenomas (Fig. 6G-H),
but evidence is limited. Noguchi et al. demonstrated inactivation of
the same AR allele in three fibroadenomas that subsequently re-
curred as phyllodes tumors,53 and another study described a fi-
broepithelial lesion with shared LOH in areas morphologically
resembling fibroadenoma and malignant phyllodes tumor.121
449
More recent targeted sequencing revealed shared mutations in a
fibroepithelial tumor with fibroadenoma-like and phyllodes tu-
mor-like areas, as well as in fibroadenoma preceding phyllodes
tumor recurrence.3,46 Nonetheless, the data overall are scarce, and
inherent intratumoral heterogeneity as an explanation for these
findings cannot be excluded.
Issues in clinical management and outcomes
Fibroadenomas of usual type generally do not recur, and those
diagnosed on core biopsy without concerning clinical behavior can be
enucleated or managed non-surgically. Treatment depends on patient
preference and risk factors. Nonsurgical options include observation
with follow-up, percutaneous vacuum-assisted biopsy, and
cryoablation.122–124 Incomplete removal with these approaches is as-
sociated with larger size (42 cm).122,123,125 Juvenile fibroadenomas
are often excised, given the rapid growth of some lesions and the
inability to distinguish them from phyllodes tumor on core biopsy.
Excision aims to preserve as much breast tissue as possible in ado-
lescent girls to allow for proper breast development.11
Phyllodes tumors are treated by surgical excision, and most do
not recur. Risk of recurrence is associated with increasing tumor
grade and is reported to be 10–17%, 14–25% and 23–30% for benign,
borderline and malignant tumors, respectively.1,63 In addition, mar-
gin status is a strong predictor of local recurrence.56,63,65,71,126,127 In a
large study, Tan et al. found that stromal cell atypia, stromal over-
growth and surgical margin status were most predictive of recur-
rence-free survival (RFS), with mitotic activity nearing statistical
significance on multivariate analysis (A.M.O.S. criteria). A nomogram
using these features was developed to help predict RFS more accu-
rately than grade or a sum of histologic features, which has since
been validated in other cohorts.63,128,129 The nomogram can be
adapted to routine practice to provide clinicians with personalized
local recurrence risk data.
In general, excision to negative margins and including a rim of
normal tissue has been recommended for phyllodes tumors.
However, adequate distance to negative margins has not been
randomly or prospectively evaluated. A 1 cm rim of uninvolved
tissue has been recommended based on retrospective analyses,
but others have shown no clear relationship between size of
margin width and recurrence or RFS, and optimal margin width
remains uncertain.56,67,71,93,126,127,130–132 Recent studies have ad-
vocated less aggressive treatment for benign phyllodes
tumors.56,67,131,133,134 Based on overall low recurrence rates and
lack of correlation with margin status, the findings can be used to
support a more conservative approach without requirement for
negative margins for benign phyllodes tumors. This is especially
relevant in cases diagnosed as cellular fibroepithelial lesion on core
biopsy and subsequently found to be benign phyllodes tumor on
excision, as the extent of initial excision (enucleation for fi-
broadenoma vs. wider excision to negative margins for phyllodes
tumor) may be less important than previously thought. However,
close follow-up is required with timely re-excision to negative
margins for any subsequent recurrence. Borderline and malignant
phyllodes tumors should be excised to negative margins.
Routine use of adjuvant radiation therapy currently has no role
in phyllodes tumor treatment, and its use is often determined on a
case-by case basis 1,135,136 Radiation may decrease local recur-
rence, but survival benefit has not been demonstrated.130,137 There
is no proven benefit for chemotherapy.135,136,138 The optimal local
treatment for phyllodes tumor continues to evolve.
450 G. Krings et al. / Seminars in Diagnostic Pathology 34 (2017) 438–452
Acknowledgments
We thank Sarah Bowman for technical expertise in preparing
the figures.
References
1. Tan PH, Tse G, Lee A, Simpson JF, Hanby AM. Fibroepithelial Tumours. In: Lakhani
SR, Ellis IO, Schnitt SJ, Tan PT, Vijver MJ, eds. WHO Classification of Tumours of the
Breast. 4th ed., Lyon, France: International Agency for Research on Cancer (IARC);
2012:141–147.
2. Lim WK, Ong CK, Tan J, et al. Exome sequencing identifies highly recurrent
MED12 somatic mutations in breast fibroadenoma. Nat Genet 2014;46:877–880.
3. Tan J, Ong CK, Lim WK, et al. Genomic landscapes of breast fibroepithelial tu-
mors. Nat Genet 2015;47:1341–1345.
4. Cani AK, Hovelson DH, McDaniel AS, et al. Next-Gen Sequencing Exposes Fre-
quent MED12 Mutations and Actionable Therapeutic Targets in Phyllodes Tu-
mors. Mol Cancer Res 2015.
5. Piscuoglio S, Ng CK, Murray M, et al. Massively parallel sequencing of phyllodes
tumours of the breast reveals actionable mutations, and TERT promoter hotspot
mutations and TERT gene amplification as likely drivers of progression. J Pathol
2016;238:508–518.
6. Liu SY, Joseph NM, Ravindranathan A, et al. Genomic profiling of malignant
phyllodes tumors reveals aberrations in FGFR1 and PI-3 kinase/RAS signaling
pathways and provides insights into intratumoral heterogeneity. Mod Pathol
2016;29:1012–1027.
7. Nozad S, Sheehan CE, Gay LM, et al. Comprehensive genomic profiling of ma-
lignant phyllodes tumors of the breast. Breast Cancer Res Treat 2017;162:597–
602.
8. Brogi E. Fibroepithelial Neoplasms. In: Hoda S, Brogi E, Koerner FC, Rosen PR, eds.
Rosen's Breast Pathology. 4th ed., Philadelphia, PA: Wolters Kluwer; 2014:1379.
9. Weaver DL, Rosenberg RD, Barlow WE, et al. Pathologic findings from the Breast
Cancer Surveillance Consortium: population-based outcomes in women under-
going biopsy after screening mammography. Cancer 2006;106:732–742.
10. Foster ME, Garrahan N, Williams S. Fibroadenoma of the breast: a clinical and
pathological study. J R Coll Surg Edinb 1988;33:16–19.
11. Pike AM, Oberman HA. Juvenile (cellular) adenofibromas. A clinicopathologic
study. Am J Surg Pathol 1985;9:730–736.
12. Song BS, Kim EK, Seol H, et al. Giant juvenile fibroadenoma of the breast: a case
report and brief literature review. Ann Pediatr Endocrinol Metab 2014;19:45–48.
13. Trapido EJ, Brinton LA, Schairer C, et al. Estrogen replacement therapy and
benign breast disease. J Natl Cancer Inst 1984;73:1101–1105.
14. Dixon JM. Cystic disease and fibroadenoma of the breast: natural history and
relation to breast cancer risk. Br Med Bull 1991;47:258–271.
15. Gupta P, Foshee S, Garcia-Morales F, et al. Fibroadenoma in male breast: case
report and literature review. Breast Dis 2011;33:45–48.
16. Kanhai RC, Hage JJ, Bloemena E, et al. Mammary fibroadenoma in a male-to-
female transsexual. Histopathology 1999;35:183–185.
17. Hilton DA, Jameson JS, Furness PN. A cellular fibroadenoma resembling a be-
nign phyllodes tumour in a young male with gynaecomastia. Histopathology
1991;18:476–477.
18. Iaria G, Pisani F, De Luca L, et al. Prospective study of switch from cyclosporine
to tacrolimus for fibroadenomas of the breast in kidney transplantation.
Transplant Proc 2010;42:1169–1170.
19. Seo YL, Choi CS, Yoon DY, et al. Benign breast diseases associated with cy-
closporine therapy in renal transplant recipients. Transplant Proc
2005;37:4315–4319.
20. Alkhunaizi AM, Ismail A, Yousif BM. Breast fibroadenomas in renal transplant
recipients. Transplant Proc 2004;36:1839–1840.
21. Williamson ME, Lyons K, Hughes LE. Multiple fibroadenomas of the breast: a
problem of uncertain incidence and management. Ann R Coll Surg Engl
1993;75:161–163.
22. Carney JA, Toorkey BC. Myxoid fibroadenoma and allied conditions (myx-
omatosis) of the breast. A heritable disorder with special associations including
cardiac and cutaneous myxomas. Am J Surg Pathol 1991;15:713–721.
23. Kuijper A, Mommers EC, van der Wall E, et al. Histopathology of fibroadenoma
of the breast. Am J Clin Pathol 2001;115:736–742.
24. Sklair-Levy M, Sella T, Alweiss T, et al. Incidence and management of complex
fibroadenomas. AJR Am J Roentgenol 2008;190:214–218.
25. Dupont WD, Page DL, Parl FF, et al. Long-term risk of breast cancer in women
with fibroadenoma. N Engl J Med 1994;331:10–15.
26. Lien HC, Huang CS, Yang YW, et al. Mutational analysis of MED12 exon 2 in a
spectrum of fibroepithelial tumours of the breast: implications for pathogen-
esis and histogenesis. Histopathology 2015.
27. Volckmar AL, Leichsenring J, Flechtenmacher C, et al. Tubular, lactating, and
ductal adenomas are devoid of MED12 Exon2 mutations, and ductal adenomas
show recurrent mutations in GNAS and the PI3K-AKT pathway. Genes Chro-
mosomes Cancer 2017;56:11–17.
28. Ross DS, Giri DD, Akram MM, et al. Fibroepithelial Lesions in the Breast of
Adolescent Females: a Clinicopathological Study of 54 Cases. Breast J
2017;23:182–192.
29. Fekete P, Petrek J, Majmudar B, et al. Fibroadenomas with stromal cellularity. A
clinicopathologic study of 21 patients. Arch Pathol Lab Med 1987;111:427–432.
30. Tay TK, Chang KT, Thike AA, et al. Paediatric fibroepithelial lesions revisited:
pathological insights. J Clin Pathol 2015;68:633–641.
31. Jacobs TW. Update on Fibroepithelial Lesions of the Breast. Surg Pathol Clin
2009;2:301–317.
32. Jacobs TW, Chen YY, Guinee Jr DG, et al. Fibroepithelial lesions with cellular
stroma on breast core needle biopsy: are there predictors of outcome on sur-
gical excision? Am J Clin Pathol 2005;124:342–354.
33. Yasir S, Gamez R, Jenkins S, et al. Significant histologic features differentiating
cellular fibroadenoma from phyllodes tumor on core needle biopsy specimens.
Am J Clin Pathol 2014;142:362–369.
34. Lee AH, Hodi Z, Ellis IO, et al. Histological features useful in the distinction of
phyllodes tumour and fibroadenoma on needle core biopsy of the breast. His-
topathology 2007;51:336–344.
35. Jacobs TW, Chen YY, Guinee DG, et al. Phyllodes tumor subsequent to a di-
agnosis of fibroadenoma on breast core needle biopsy: frequency and char-
acteristics. Mod Pathol 2014;27(Supplement 2):56A.
36. Yamaguchi R, Tanaka M, Mizushima Y, et al. Myxomatous fibroadenoma of the
breast: correlation with clinicopathologic and radiologic features. Hum Pathol
2011;42:419–423.
37. Skenderi F, Krakonja F, Vranic S. Infarcted fibroadenoma of the breast: report of
two new cases with review of the literature. Diagn Pathol 2013;8:38.
38. Ichihara S, Matsuyama T, Kubo K, et al. Infarction of breast fibroadenoma in a
postmenopausal woman. Pathol Int 1994;44:398–400.
39. Pinto RG, Couto F, Mandreker S. Infarction after fine needle aspiration. A report
of four cases. Acta Cytol 1996;40:739–741.
40. Oh YJ, Choi SH, Chung SY, et al. Spontaneously infarcted fibroadenoma mi-
micking breast cancer. J Ultrasound Med 2009;28:1421–1423.
41. Sawyer EJ, Hanby AM, Poulsom R, et al. Beta-catenin abnormalities and asso-
ciated insulin-like growth factor overexpression are important in phyllodes
tumours and fibroadenomas of the breast. J Pathol 2003;200:627–632.
42. Sapino A, Bosco M, Cassoni P, et al. Estrogen receptor-beta is expressed in
stromal cells of fibroadenoma and phyllodes tumors of the breast. Mod Pathol
2006;19:599–606.
43. Je EM, Kim MR, Min KO, et al. Mutational analysis of MED12 exon 2 in uterine
leiomyoma and other common tumors. Int J Cancer 2012;131:E1044–E1047.
44. Makinen N, Mehine M, Tolvanen J, et al. MED12, the mediator complex subunit
12 gene, is mutated at high frequency in uterine leiomyomas. Science
2011;334:252–255.
45. Pfarr N, Kriegsmann M, Sinn P, et al. Distribution of MED12 mutations in fi-
broadenomas and phyllodes tumors of the breast–implications for tumor biology
and pathological diagnosis. Genes Chromosomes Cancer 2015;54:444–452.
46. Piscuoglio S, Murray M, Fusco N, et al. MED12 somatic mutations in fi-
broadenomas and phyllodes tumours of the breast. Histopathology
2015;67:719–729.
47. Tan WJ, Chan JY, Thike AA, et al. MED12 protein expression in breast fi-
broepithelial lesions: correlation with mutation status and oestrogen receptor
expression. J Clin Pathol 2016;69:858–865.
48. Mishima C, Kagara N, Tanei T, et al. Mutational analysis of MED12 in fi-
broadenomas and phyllodes tumors of the breast by means of targeted next-
generation sequencing. Breast Cancer Res Treat 2015;152:305–312.
49. Noguchi S, Motomura K, Inaji H, et al. Clonal analysis of fibroadenoma and
phyllodes tumor of the breast. Cancer Res 1993;53:4071–4074.
50. Kobayashi S, Iwase H, Kuzushima T, et al. Consecutively occurring multiple
fibroadenomas of the breast distinguished from phyllodes tumors by clonality
analysis of stromal tissue. Breast Cancer 1999;6:201–206.
51. Kasami M, Vnencak-Jones CL, Manning S, et al. Monoclonality in fi-
broadenomas with complex histology and phyllodal features. Breast Cancer Res
Treat 1998;50:185–191.
52. Kuijper A, Buerger H, Simon R, et al. Analysis of the progression of fi-
broepithelial tumours of the breast by PCR-based clonality assay. J Pathol
2002;197:575–581.
53. Noguchi S, Yokouchi H, Aihara T, et al. Progression of fibroadenoma to phyl-
lodes tumor demonstrated by clonal analysis. Cancer 1995;76:1779–1785.
54. Lozada JRPF, Burke KA, Maguire A, et al. Massively parallel sequencing analysis
of myxoid fibroadenomas reveals a genomic landscape distinct from that of
conventional fibroadenomas. Mod Pathol 2017;30(supplement 2):57A.
55. Karim RZ, Gerega SK, Yang YH, et al. Phyllodes tumours of the breast: a clin-
icopathological analysis of 65 cases from a single institution. Breast
2009;18:165–170.
56. Kim S, Kim JY, Kim do H, et al. Analysis of phyllodes tumor recurrence ac-
cording to the histologic grade. Breast Cancer Res Treat 2013;141:353–363.
57. Gordon PB, Gagnon FA, Lanzkowsky L. Solid breast masses diagnosed as fi-
broadenoma at fine-needle aspiration biopsy: acceptable rates of growth at
long-term follow-up. Radiology 2003;229:233–238.
58. Liberman L, Bonaccio E, Hamele-Bena D, et al. Benign and malignant phyllodes
tumors: mammographic and sonographic findings. Radiology 1996;198:121–124.
59. Buchberger W, Strasser K, Heim K, et al. Phylloides tumor: findings on
mammography, sonography, and aspiration cytology in 10 cases. AJR Am J
Roentgenol 1991;157:715–719.
60. Chao TC, Lo YF, Chen SC, et al. Sonographic features of phyllodes tumors of the
breast. Ultrasound Obstet Gynecol 2002;20:64–71.
61. Wurdinger S, Herzog AB, Fischer DR, et al. Differentiation of phyllodes breast
tumors from fibroadenomas on MRI. AJR Am J Roentgenol 2005;185:1317–1321.
62. Keelan PA, Myers JL, Wold LE, et al. Phyllodes tumor: clinicopathologic review
of 60 patients and flow cytometric analysis in 30 patients. Hum Pathol
 G. Krings et al. / Seminars in Diagnostic Pathology 34 (2017) 438–452
1992;23:1048–1054.
63. Tan PH, Thike AA, Tan WJ, et al. Predicting clinical behaviour of breast phyl-
lodes tumours: a nomogram based on histological criteria and surgical mar-
gins. J Clin Pathol 2012;65:69–76.
64. Norris HJ, Taylor HB. Relationship of histologic features to behavior of cysto-
sarcoma phyllodes. Analysis of ninety-four cases Cancer 1967;20:2090–2099.
65. Cohn-Cedermark G, Rutqvist LE, Rosendahl I, et al. Prognostic factors in cy-
stosarcoma phyllodes. A clinicopathologic study of 77 patients. Cancer
1991;68:2017–2022.
66. Moffat CJ, Pinder SE, Dixon AR, et al. Phyllodes tumours of the breast: a clin-
icopathological review of thirty-two cases. Histopathology 1995;27:205–218.
67. Tan EY, Tan PH, Yong WS, et al. Recurrent phyllodes tumours of the breast:
pathological features and clinical implications. ANZ J Surg 2006;76:476–480.
68. Tan PH, Jayabaskar T, Chuah KL, et al. Phyllodes tumors of the breast: the role
of pathologic parameters. Am J Clin Pathol 2005;123:529–540.
69. Gullett NP, Rizzo M, Johnstone PA. National surgical patterns of care for pri-
mary surgery and axillary staging of phyllodes tumors. Breast J 2009;15:41–44.
70. Macdonald OK, Lee CM, Tward JD, et al. Malignant phyllodes tumor of the
female breast: association of primary therapy with cause-specific survival from
the Surveillance, Epidemiology, and End Results (SEER) program. Cancer
2006;107:2127–2133.
71. Barrio AV, Clark BD, Goldberg JI, et al. Clinicopathologic features and long-term
outcomes of 293 phyllodes tumors of the breast. Ann Surg Oncol 2007;14:2961–2970.
72. Chua CL, Thomas A, Ng BK. Cystosarcoma phyllodes–Asian variations. Aust N Z J
Surg 1988;58:301–305.
73. Keelan PA, Myers JL, Wold LE, et al. Phyllodes Tumor - Clinicopathological
Review of 60 Patients and Flow Cytometric Analysis in 30 Patients. Human
Pathol 1992;23:1048–1054.
74. Nielsen VT, Andreasen C. Phyllodes tumour of the male breast. Histopathology
1987;11:761–762.
75. Konstantakos AK, Graham DJ. Cystosarcoma phyllodes tumors in men. Am Surg
2003;69:808–811.
76. Giacomazzi J, Koehler-Santos P, Palmero EI, et al. A TP53 founder mutation, p.
R337H, is associated with phyllodes breast tumors in Brazil. Virchows Arch
2013;463:17–22.
77. Foucar CE, Hardy A, Siziopikou KP, et al. A mother and daughter with phyllodes
tumors of the breast. Clin Breast Cancer 2012;12:373–377.
78. Birch JM, Alston RD, McNally RJ, et al. Relative frequency and morphology of
cancers in carriers of germline TP53 mutations. Oncogene 2001;20:4621–4628.
79. Powell CM, Rosen PP. Adipose differentiation in cystosarcoma phyllodes. A
study of 14 cases. Am J Surg Pathol 1994;18:720–727.
80. Tsang AK, Chan SK, Lam CC, et al. Phyllodes tumours of the breast - differ-
entiating features in core needle biopsy. Histopathology 2011;59:600–608.
81. Choi J, Koo JS. Comparative study of histological features between core needle
biopsy and surgical excision in phyllodes tumor. Pathol Int 2012;62:120–126.
82. Krings G, Chen YY. Fibroepithelial Lesions. In: Shin S, ed. A Comprehensive Guide
to Core Needle Biopsies of the Breast. 1st ed., Switzerland: Spinger International;
2016:241–319.
83. Chaney AW, Pollack A, McNeese MD, et al. Primary treatment of cystosarcoma
phyllodes of the breast. Cancer 2000;89:1502–1511.
84. Jones AM, Mitter R, Springall R, et al. A comprehensive genetic profile of
phyllodes tumours of the breast detects important mutations, intra-tumoral
genetic heterogeneity and new genetic changes on recurrence. J Pathol
2008;214:533–544.
85. Kracht J, Sapino A, Bussolati G. Malignant phyllodes tumor of breast with lung
metastases mimicking the primary. Am J Surg Pathol 1998;22:1284–1290.
86. Burga AM, Tavassoli FA. Periductal stromal tumor: a rare lesion with low-grade
sarcomatous behavior. Am J Surg Pathol 2003;27:343–348.
87. Lawton TJ, Acs G, Argani P, et al. Interobserver variability by pathologists in the
distinction between cellular fibroadenomas and phyllodes tumors. Int J Surg
Pathol 2014;22:695–698.
88. Tan BY, Acs G, Apple SK, et al. Phyllodes tumours of the breast: a consensus
review. Histopathology 2016;68:5–21.
89. Tse GM, Law BK, Chan KF, et al. Multinucleated stromal giant cells in mammary
phyllodes tumours. Pathology 2001;33:153–156.
90. Jara-Lazaro AR, Akhilesh M, Thike AA, et al. Predictors of phyllodes tumours on
core biopsy specimens of fibroepithelial neoplasms. Histopathology
2010;57:220–232.
91. Resetkova E, Khazai L, Albarracin CT, et al. Clinical and radiologic data and core
needle biopsy findings should dictate management of cellular fibroepithelial
tumors of the breast. Breast J 2010;16:573–580.
92. Tan WJ, Cima I, Choudhury Y, et al. A five-gene reverse transcription-PCR assay
for pre-operative classification of breast fibroepithelial lesions. Breast Cancer
Res 2016;18:31.
93. National Comprehensive Cancer Network (NCCN) Guidelines Version 1. 2015
Phyllodes Tumor. Fort Washington, P.A.2015. Available from: 〈http://www.nccn.
org/professionals/physician_gls/f_guidelines.asp〉.
94. Lim SZ, Selvarajan S, Thike AA, et al. Breast sarcomas and malignant phyllodes
tumours: comparison of clinicopathological features, treatment strategies,
prognostic factors and outcomes. Breast Cancer Res Treat 2016;159:229–244.
95. Cimino-Mathews A, Sharma R, Illei PB, et al. A subset of malignant phyllodes
tumors express p63 and p40: a diagnostic pitfall in breast core needle biopsies.
Am J Surg Pathol 2014;38:1689–1696.
96. Dunne B, Lee AH, Pinder SE, et al. An immunohistochemical study of meta-
plastic spindle cell carcinoma, phyllodes tumor and fibromatosis of the breast.
Hum Pathol 2003;34:1009–1015.
451
97. Adem C, Reynolds C, Adlakha H, et al. Wide spectrum screening keratin as a
marker of metaplastic spindle cell carcinoma of the breast: an im-
munohistochemical study of 24 patients. Histopathology 2002;40:556–562.
98. Carter MR, Hornick JL, Lester S, et al. Spindle cell (sarcomatoid) carcinoma of
the breast: a clinicopathologic and immunohistochemical analysis of 29 cases.
Am J Surg Pathol 2006;30:300–309.
99. Aranda FI, Laforga JB, Lopez JI. Phyllodes tumor of the breast. An im-
munohistochemical study of 28 cases with special attention to the role of
myofibroblasts. Pathol Res Pract 1994;190:474–481.
100. Chia Y, Thike AA, Cheok PY, et al. Stromal keratin expression in phyllodes
tumours of the breast: a comparison with other spindle cell breast lesions. J
Clin Pathol 2012;65:339–347.
101. Lee AH. Recent developments in the histological diagnosis of spindle cell
carcinoma, fibromatosis and phyllodes tumour of the breast. Histopathology
2008;52:45–57.
102. Moore T, Lee AH. Expression of CD34 and bcl-2 in phyllodes tumours, fi-
broadenomas and spindle cell lesions of the breast. Histopathology
2001;38:62–67.
103. Cimino-Mathews A, Subhawong AP, Elwood H, et al. Neural crest transcrip-
tion factor Sox10 is preferentially expressed in triple-negative and metaplastic
breast carcinomas. Hum Pathol 2013;44:959–965.
104. Cimino-Mathews A, Subhawong AP, Illei PB, et al. GATA3 expression in breast
carcinoma: utility in triple-negative, sarcomatoid, and metastatic carcinomas.
Hum Pathol 2013;44:1341–1349.
105. Yoshida M, Sekine S, Ogawa R, et al. Frequent MED12 mutations in phyllodes
tumours of the breast. Br J Cancer 2015;112:1703–1708.
106. Tse GM, Lee CS, Kung FY, et al. Hormonal receptors expression in epithelial
cells of mammary phyllodes tumors correlates with pathologic grade of the
tumor: a multicenter study of 143 cases. Am J Clin Pathol 2002;118:522–526.
107. Sawyer EJ, Hanby AM, Rowan AJ, et al. The Wnt pathway, epithelial-stromal
interactions, and malignant progression in phyllodes tumours. J Pathol
2002;196:437–444.
108. Tsang JY, Mendoza P, Lam CC, et al. Involvement of alpha- and beta-catenins
and E-cadherin in the development of mammary phyllodes tumours. Histo-
pathology 2012;61:667–674.
109. Dietrich CU, Pandis N, Rizou H, et al. Cytogenetic findings in phyllodes tumors
of the breast: karyotypic complexity differentiates between malignant and
benign tumors. Hum Pathol 1997;28:1379–1382.
110. Lae M, La Rosa P, Mandel J, et al. Whole-genome profiling helps to classify
phyllodes tumours of the breast. J Clin Pathol 2016;69:1081–1087.
111. Ang MK, Ooi AS, Thike AA, et al. Molecular classification of breast phyllodes
tumors: validation of the histologic grading scheme and insights into malig-
nant progression. Breast Cancer Res Treat 2011;129:319–329.
112. Lae M, Vincent-Salomon A, Savignoni A, et al. Phyllodes tumors of the breast
segregate in two groups according to genetic criteria. Mod Pathol
2007;20:435–444.
113. Lu YJ, Birdsall S, Osin P, et al. Phyllodes tumors of the breast analyzed by
comparative genomic hybridization and association of increased 1q copy
number with stromal overgrowth and recurrence. Genes Chromosomes Cancer
1997;20:275–281.
114. Lv S, Niu Y, Wei L, et al. Chromosomal aberrations and genetic relations in
benign, borderline and malignant phyllodes tumors of the breast: a comparative
genomic hybridization study. Breast Cancer Res Treat 2008;112:411–418.
115. Tan WJ, Lai JC, Thike AA, et al. Novel genetic aberrations in breast phyllodes
tumours: comparison between prognostically distinct groups. Breast Cancer
Res Treat 2014;145:635–645.
116. Ng CC, Tan J, Ong CK, et al. MED12 is frequently mutated in breast phyllodes
tumours: a study of 112 cases. J Clin Pathol 2015;68:685–691.
117. Yoon N, Bae GE, Kang SY, et al. Frequency of MED12 mutations in phyllodes
tumors: inverse correlation with histologic grade. Genes Chromosomes Cancer
2016;55:495–504.
118. Lien HC, Huang CS, Yang YW, et al. MED12 exon 2 mutation as a highly
sensitive and specific marker in distinguishing phyllodes tumours from other
spindle neoplasms of the breast. APMIS 2016;124:356–364.
119. Yoshida M, Ogawa R, Yoshida H, et al. TERT promoter mutations are frequent
and show association with MED12 mutations in phyllodes tumors of the
breast. Br J Cancer 2015;113:1244–1248.
120. Lyle PL, Bridge JA, Simpson JF, et al. Liposarcomatous differentiation in ma-
lignant phyllodes tumours is unassociated with MDM2 or CDK4 amplification.
Histopathology 2016;68:1040–1045.
121. Hodges KB, Abdul-Karim FW, Wang M, et al. Evidence for transformation of
fibroadenoma of the breast to malignant phyllodes tumor. Appl Im-
munohistochem Mol Morphol 2009;17:345–350.
122. Sperber F, Blank A, Metser U, et al. Diagnosis and treatment of breast fi-
broadenomas by ultrasound-guided vacuum-assisted biopsy. Arch Surg
2003;138:796–800.
123. Kaufman CS, Littrup PJ, Freeman-Gibb LA, et al. Office-based cryoablation of
breast fibroadenomas with long-term follow-up. Breast J 2005;11:344–350.
124. Nurko J, Mabry CD, Whitworth P, et al. Interim results from the Fi-
broAdenoma Cryoablation Treatment Registry. Am J Surg 2005;190:647–651
[discussion 651-2].
125. Grady I, Gorsuch H, Wilburn-Bailey S. Long-term outcome of benign fi-
broadenomas treated by ultrasound-guided percutaneous excision. Breast J
2008;14:275–278.
126. Chen WH, Cheng SP, Tzen CY, et al. Surgical treatment of phyllodes tumors of
the breast: retrospective review of 172 cases. J Surg Oncol 2005;91:185–194.
452 G. Krings et al. / Seminars in Diagnostic Pathology 34 (2017) 438–452
127. Mangi AA, Smith BL, Gadd MA, et al. Surgical management of phyllodes tu-
mors. Arch Surg 1999;134:487–492 [discussion 492-3].
128. Chng TW, Lee JY, Lee CS, et al. Validation of the Singapore nomogram for
outcome prediction in breast phyllodes tumours: an Australian cohort. J Clin
Pathol 2016;69:1124–1126.
129. Nishimura R, Tan PH, Thike AA, et al. Utility of the Singapore nomogram for
predicting recurrence-free survival in Japanese women with breast phyllodes
tumours. J Clin Pathol 2014;67:748–750.
130. Belkacemi Y, Bousquet G, Marsiglia H, et al. Phyllodes tumor of the breast. Int
J Radiat Oncol Biol Phys 2008;70:492–500.
131. Teo JY, Cheong CS, Wong CY. Low local recurrence rates in young Asian pa-
tients with phyllodes tumours: less is more. ANZ J Surg 2012;82:325–328.
132. Yom CK, Han W, Kim SW, et al. Reappraisal of conventional risk stratification
for local recurrence based on clinical outcomes in 285 resected phyllodes
tumors of the breast. Ann Surg Oncol 2015;22:2912–2918.
133. Moutte A, Chopin N, Faure C, et al. Surgical management of benign and
borderline phyllodes tumors of the breast. Breast J 2016;22:547–552.
134. Cowan ML, Argani P, Cimino-Mathews A. Benign and low-grade fibroepithelial
neoplasms of the breast have low recurrence rate after positive surgical
margins. Mod Pathol 2016;29:259–265.
135. Khosravi-Shahi P. Management of non metastatic phyllodes tumors of the
breast: review of the literature. Surg Oncol 2011;20:e143–e148.
136. Guillot E, Couturaud B, Reyal F, et al. Management of phyllodes breast tumors.
Breast J 2011;17:129–137.
137. Barth Jr RJ, Wells WA, Mitchell SE, et al. A prospective, multi-institutional
study of adjuvant radiotherapy after resection of malignant phyllodes tumors.
Ann Surg Oncol 2009;16:2288–2294.
138. Telli ML, Horst KC, Guardino AE, et al. Phyllodes tumors of the breast: natural
history, diagnosis, and treatment. J Natl Compr Canc Netw 2007;5:324–
330.