Phyllodes tumors of the breast

Authors
Ana M Grau, MD, FACS
A Bapsi Chakravarthy, MD
Rashmi Chugh, MD
Section Editors
Lori J Pierce, MD
Daniel F Hayes, MD
Anees B Chagpar, MD, MSc, MA, MPH, FACS, FRCS(C)
Deputy Editor
Rosemary B Duda, MD, MPH, FACS
Disclosures
All topics are updated as new evidence becomes available and our peer review
process is complete.
Literature review current through: Jan 2014. | This topic last updated: 18, 2012.
INTRODUCTION Phyllodes tumors are uncommon fibroepithelial breast tumors
that are capable of a diverse range of biologic behavior. In their least aggressive form,
they behave similarly to benign fibroadenomas, although with a propensity to recur
locally following excision without wide margins. At the other end of the spectrum are
tumors that metastasize distantly, sometimes degenerating histologically into
sarcomatous lesions that lack an epithelial component [1,2].
The terminology of phyllodes tumors has evolved. All such tumors were originally
called "cystosarcoma phyllodes" by Johannes Muller in 1838 [1]. However, they only
occasionally have cystic components, and they are not true sarcomas by either cellular
origin or biologic behavior. The term "phyllodes", which means leaf-like, describes
the typical papillary projections that are seen on pathologic examination. Since the
original description, over 60 synonyms have been applied to this entity until the
adoption of the term phyllodes tumors by the World Health Organization [3,4].
EPIDEMIOLOGY AND RISK FACTORS Phyllodes tumors account for fewer
than 0.5 percent of all breast malignancies [4,5]. Given their rarity, epidemiologic data
are scant. In a study from Los Angeles county over a 17 year period, the average
annual incidence rate was 2.1 per million women, and there was a higher incidence in
Latina whites, as compared to non-Latina whites, Asians, and African American
women [6].
The vast majority occur in women, in whom the median age at presentation is 42 to
45 (range 10 to 82 years) [3,6-8]. Data indicate that the tumor grade increases with
mean age at diagnosis [9]. Some case reports describe these tumors in men, usually in
association with gynecomastia [3].
No etiologic or predisposing factors have been associated with phyllodes tumors, with
the exception of Li-Fraumeni syndrome, a rare autosomal dominant condition that is
characterized by the development of multiple tumors [10]. (See "BRCA1 and
BRCA2: Prevalence and risks for breast and ovarian cancer" and "Li-Fraumeni
syndrome".)

Some believe that phyllodes tumors arise from benign epithelial fibroadenomas due to
their close histologic resemblance and molecular similarities [1,3,11]. However, this
remains an ongoing debate. (See "Overview of benign breast disease".)
CLINICAL PRESENTATION AND DIAGNOSIS Phyllodes tumors are generally
first identified as a breast mass or an abnormal mammographic finding.
Physical examination On examination, most patients have a smooth, multinodular,
well-defined, firm mass that is mobile and painless [1,7]. Tumor size is variable,
ranging from 1 to 41 cm (average 4 to 7 cm) [4,8]. Shiny, stretched, and attenuated
skin may be seen overlying a large tumor [1]. Nipple retraction, ulceration, chest wall
fixation, and bilateral disease are rare but described [1,12].
Tumors may be slow or rapidly growing, or they may exhibit a biphasic growth
pattern. As they grow, phyllodes tumors can distort the breast or cause superficial
ulceration through pressure necrosis. The mass may be visible on inspection,
especially if it expands quickly.
Although palpable axillary lymphadenopathy can be identified in up to 20 percent of
patients, metastatic involvement of lymph nodes is rare [4,7].
Imaging The typical appearance of a phyllodes tumor on mammography is a
smooth, polylobulated mass resembling a fibroadenoma [1]. Approximately 20
percent of phyllodes tumors present as a nonpalpable mass identified on screening
mammography [13]. (See "Breast imaging: Mammography and ultrasonography" and
"Diagnostic evaluation of women with suspected breast cancer".)
Suspicion for a phyllodes tumor rather than a fibroadenoma is based on large tumor
size at presentation or rapid growth [1]. Patients with a suspicious lesion on
mammography should have an ultrasound examination. Phyllodes lesions are
primarily solid, hypoechoic and well circumscribed on ultrasonography. Although not
always present, cystic areas within the mass may increase the level of suspicion for
phyllodes tumors [14].
The role of magnetic resonance imaging (MRI) in the diagnosis and management of
phyllodes tumors is not clear [15]. A retrospective study of 30 patients with biopsy
confirmed phyllodes tumors showed that malignant phyllodes tumors are seen as
well-circumscribed tumors with irregular walls, high signal intensity on T1-weighted
images and low signal intensity on T2-weighted images [16]. Cystic change may be
seen as well. Interestingly, a rapid enhancement pattern is seen more commonly with
benign rather than malignant phyllodes tumors, which is the opposite of the pattern
seen with adenocarcinomas of the breast [16,17].
When the diagnosis of a phyllodes tumor has been made on core biopsy, breast MRI
may prove helpful in determining the extent of disease and facilitating pre-operative
planning [17]. However, the use of breast MRI in surgical planning for phyllodes
tumors is controversial as there are very little data on its role in this setting as they are
so rare.

Biopsy Fine needle aspiration biopsy has been associated with high false negative
results and low overall accuracy for the diagnosis of phyllodes tumors [18]. However,
special attention to three major cytological features (fibromyxoid stromal fragments
with spindle nuclei, fibroblastic pavements, and spindle cells of fibroblastic nature)
can improve the diagnosis of phyllodes tumor on FNA [19].
Core needle biopsy is the preferred method for making a diagnosis [20]. There are
some features that are useful in distinguishing phyllodes tumors and fibroadenomas
on core biopsy. These include increased cellularity, mitosis, stromal overgrowth, and
fragmentation (stroma with epithelium at one or both ends of the fragment) of the
biopsy specimen.
A core needle biopsy of a phyllodes tumor can result in a 25 to 30 percent false
negative rate [21-23]. For this reason, if a solid mass has a benign biopsy but
subsequently exhibits rapid growth or becomes symptomatic, excisional biopsy
should be performed. Additionally, if a core biopsy is indeterminate, then an
excisional biopsy will be necessary to make the diagnosis. (See "Breast biopsy".)
PATHOLOGY Grossly, phyllodes tumors are round to oval multinodular masses
with a grayish white appearance that resemble the head of a cauliflower; they may be
indistinguishable from fibroadenomas (picture 1) [1]. Phyllodes tumors grow radially
creating a pseudocapsule through which tongues of stroma may protrude and grow
into adjacent breast tissue [24]. Necrosis and hemorrhage can occur in larger tumors
[1].
Microscopically, the range of appearances covers the spectrum from resembling a
benign fibroadenoma to a high-grade sarcoma. The characteristic leaf-like architecture
consists of elongated cleft-like spaces that contain papillary projections of epitheliallined stroma with varying degrees of hyperplasia and atypia (figure 1) [3].The stromal
elements are a key component in the differentiation of phyllodes tumors from
fibroadenomas and in distinguishing a benign from a malignant phyllodes tumor [7].
Histologically, phyllodes tumors are classified as benign, borderline or malignant
[1,4,25]. The most commonly accepted criteria used for classification of benign
versus malignant tumors are as follows [4,6,7,26,27]:
The degree of stromal cellular atypia

Mitotic activity
Infiltrative as compared to circumscribed tumor margins
Presence or absence of stromal overgrowth (ie, presence of pure stroma devoid
of epithelium)

In most large series, more than 50 percent of phyllodes tumors are classified as benign
[1,26]. Approximately 25 percent of phyllodes tumors are malignant, although this
figure varies significantly depending on the series [1,2,28]. The classification criteria
are summarized here [1]:

Benign phyllodes tumors are characterized by increased stromal cellularity

with mild to moderate cellular atypia, circumscribed tumor margins and low

mitotic rate (less than 4 mitoses per 10 high power fields) and lack of stromal
overgrowth.
Borderline tumors have a greater degree of stromal cellularity and atypia, a
mitotic rate from 4 to 9 mitosis per 10 high power fields, microscopic
infiltrative borders, and lack of stromal overgrowth.
Malignant phyllodes tumors are characterized by marked stromal cellularity
and atypia, infiltrative margins, high mitotic rate (more than 10 mitosis per 10
high power fields examined), and by the presence of stromal overgrowth
[4,7,26,27].

Some authors have suggested that these histologically defined categories may not
reliably predict clinical behavior [2,8]. When strict adherence to well-established
histologic criteria are used, benign and borderline phyllodes tumors rarely recur
following wide excision [29]. In a series of 443 women treated for phyllodes tumor,
multivariate analysis was performed on a subset of 146 patients for whom there was
no missing data and all variables could be analyzed. Patients with benign tumors had
improved local control and disease-free survival compared to patients with borderline
and malignant lesions [30].
Stromal overgrowth is consistently associated with aggressive (metastatic) behavior
[2,31]. Most clinically malignant/metastatic phyllodes tumors reported have had
overgrowth of one or several sarcomatous elements. These include liposarcoma,
undifferentiated/unclassified sarcoma (formerly included within the terms malignant
fibrous histiocytoma [MFH] and undifferentiated pleomorphic sarcoma [UPS], and
now a separate soft tissue sarcoma category with an undifferentiated pleomorphic
variant [32]), rhabdosarcoma, and chondrosarcoma [33,34]. Close examination of the
stroma is imperative as the sarcomatous component may be present in only a small
portion of the phyllodes tumor [24]. (See "Clinical presentation, histopathology,
diagnostic evaluation, and staging of soft tissue sarcoma", section on
'Histopathology'.)
Evaluation of tumor markers such as p53, Ki-67, epidermal growth factor receptors,
c-kit, platelet-derived growth factor and others in phyllodes tumors has failed to
adequately predict outcomes [24]. The expression of estrogen and progesterone
receptors is common in the epithelial component but uncommon in the stromal
component of phyllodes tumors [12].
TREATMENT Given the small number of patients with phyllodes tumors,
treatment principles are based mainly on retrospective series and case reports.
Because of their clinical behavior and prognosis, phyllodes tumors should be treated
as primary breast sarcomas rather than infiltrating ductal carcinomas [35].
Surgical resection Based upon a retrospective review of 164 patients, surgical
approach should include a wide local excision with histologic margins negative for
malignant cells [36]. Other studies suggest a histologic margin of at least 1 cm, which
is much larger than what is required for invasive or in situ breast cancer [2,4,37].
Unfortunately, local excision without attention to margins is often performed,
particularly since phyllodes tumors are often misdiagnosed as fibroadenomas
preoperatively. Recurrence rates are unacceptably high following either local excision
or enucleation without negative margins [29,38]. Breast conserving therapy is

appropriate for nonmalignant as well as malignant lesions as long as adequate margins

can be achieved [2,4,13]. Reexcision is indicated when necessary to ensure acceptable
margins [4,5,13,14,25,29,30,35,37-40].
Several reports indicate that wide excision yields local recurrence rates of 8 percent
for benign phyllodes tumors and 21 to 36 percent for borderline and malignant tumors
[29,37]. When appropriate margins are not obtained the recurrence rates are much
higher. In a retrospective review of 48 women with high-grade malignant phyllodes
tumors, 10 patients were treated with local excision (margins <1 cm), 14 with wide
local excision (margins 1 cm) and 24 with mastectomy [38]. Average tumor size was
7.8 cm and median follow up was 9 years. The recurrence rates were 60 percent for
those treated with local excision only as compared with 28 percent for those who were
treated with wide local excision with appropriate margins. Local recurrence and
cancer-specific survival were related to tumor size and excision margins.
Even large tumors may be effectively treated with breast conservation without
compromising cancer-specific survival [13]. In data from the Surveillance,
Epidemiology and End Results (SEER) database on 821 women being treated for
malignant phyllodes tumors, mastectomy and wide excision were performed in 52
percent and 48 percent of women respectively. Wide excision was associated with
equivalent or improved cause-specific survival relative to mastectomy, regardless of
tumor size.
Axillary dissection is usually not required since axillary lymph node involvement is
only rarely reported, even with malignant tumors [5,7,13,39,41]. In the SEER
database cited above, only eight of 498 women with known lymph node status had
involved nodes [13].
Radiation Adjuvant radiotherapy (RT) for phyllodes tumors is controversial.
Radiotherapy is unnecessary for benign phyllodes tumors that are widely excised.
However, some data suggest that adjuvant RT should be considered for patients with
histologically malignant phyllodes tumors [26-28,41]:

A large retrospective study of patients with malignant phyllodes tumors treated

with surgical resection alone revealed suboptimal five-year local control rates
(79 percent in 169 patients treated with wide excision and 91 percent in 207
patients treated with mastectomy) [42]. The authors concluded that for patients
with malignant phyllodes tumors, particularly over 2 cm in diameter and
treated with wide excision alone, adjuvant RT should be strongly considered.
One important limitation of this study is the lack of information about margin
status.
In a study of 443 women treated for phyllodes tumor, RT was associated with
a superior local control rate at 10 years, from 59 percent to 86 percent for
borderline and malignant phyllodes tumors [30].
In a prospective multi-institutional study of adjuvant RT in 46 patients with
borderline malignant or malignant phyllodes tumors treated with breast
conserving surgery followed by RT, there were no local recurrences with a
median follow up of 56 months [37]. Two patients with malignant phyllodes
tumor died of metastatic disease.

Taken together, these results indicate that adjuvant RT appears to be effective in

decreasing recurrences after breast conserving resection for borderline or malignant
phyllodes tumors. Most agree that adjuvant RT is appropriate when it is not possible
to obtain a wide margin of 1 cm of resection. It is also important to remember that,
for some tumors a 1 cm margin may not be possible even with a total mastectomy, due
to size or location. In such patients, radiation may be indicated even after a
mastectomy.
There is less agreement about the role of adjuvant RT when wide margins 1 cm can
be obtained. Available data indicates that RT will substantially reduce recurrence for
these patients [37]. We suggest RT in this setting but recognize that this is not
uniformly recommended by others. Further studies are needed to determine when
adjuvant RT should be advised in the treatment of phyllodes tumors. (See "Adjuvant
radiation therapy for women with newly diagnosed, non-metastatic breast cancer".)
Chemotherapy The benefit of adjuvant chemotherapy is controversial. There have
been no randomized studies of adjuvant therapy specifically in phyllodes tumors. An
observational study included 28 patients with malignant phyllodes tumors treated over
a 10-year period (1993-2003) with either adjuvant doxorubicin plus dacarbazine or
observation alone after surgical resection. Treatment was based upon patient
preference [43]. There was no difference in relapse-free survival between the two
groups. However, the study was small, retrospective, and uncontrolled, and did not
utilize ifosfamide in combination with doxorubicin (which is superior to dacarbazine
plus doxorubicin in other soft tissue sarcomas). The likely bias is that patients with
more aggressive disease would opt for treatment while those with more favorable
disease might choose observation.
Based on limited data and experiences in soft tissue sarcoma, adjuvant chemotherapy
should be administered only for a minority of patients with large (>5 cm), high-risk or
recurrent malignant tumors, and only after a thorough discussion about the risks and
benefits of treatment. Patients with benign or borderline phyllodes tumors should not
be offered chemotherapy. Guidelines for treating sarcomas rather than
adenocarcinomas of the breast should be followed. (See "Adjuvant and neoadjuvant
chemotherapy for soft tissue sarcoma of the extremities".)
Hormone therapy Hormone therapy is not effective for phyllodes tumors despite
the presence of positive hormone receptors in the epithelial component of some of
these tumors [12,44]. The stromal component is the principle neoplastic cell
population responsible for the metastatic behavior in these tumors and expresses
primarily estrogen receptor beta as opposed to the alpha receptor expressed in
adenocarcinomas of the breast [45,46].
PROGNOSIS The majority of patients with benign and borderline phyllodes
tumors are cured with surgery. The survival rate for malignant phyllodes tumors is
reported as approximately 60 to 80 percent at 5 years [2,13,35].
The impact of histology on survival was explored in the SArcoma and PHYllode
Retrospective (SAPHYR) Study, a retrospective study of 70 patients with primary
breast sarcomas and phyllodes tumors treated from 1966 to 2004 [35]. The overall
three year survival rate for combined benign and borderline tumors was 100 percent.

The overall three year survival rate for malignant phyllodes tumors was 54 percent,
similar to that of nonangiosarcoma primary breast sarcomas (60 percent).
Similarly, in a retrospective study of 101 patients treated between 1944 and 1998, the
overall survival for patients with combined benign and borderline tumors was 91
percent at 5 years. The five year survival rate for malignant phyllodes tumors was 82
percent [2]. Eight patients in this series developed distant metastases (seven of whom
had tumors classified as histologically malignant, and one benign); all of these had
stromal overgrowth, and six were 5 cm in size.
In another retrospective review of 293 phyllodes tumors, treated between 1954 and
2005, five patients developed distant disease, all of these had infiltrative borders,
marked stromal overgrowth, marked stromal cellularity, high mitotic count, and
necrosis and were 7 cm in size. [8]. Of note, six of the locally recurrent benign
phyllodes tumors recurred as malignant.
There are several case reports documenting the ability of benign tumors to undergo
malignant transformation, which points to the dilemma that there are no absolute
predictive factors for these rare tumors [2,8,28,47]. However, in the majority of cases,
when strict adherence to established histological classification criteria are followed
and adequate surgical margins are obtained, benign and borderline phyllodes tumors
rarely recur [24,29].
ADVANCED AND RECURRENT DISEASE
Local recurrence When tumors recur, they typically recur locally within two years
of initial excision [4,12]. Some series have found that time to local recurrence is
shorter for patients with malignant phyllodes compared with patients with benign and
borderline phyllodes [4].
Locally recurrent disease is best treated with re-excision with wide margins or
mastectomy followed by RT to help avoid the morbidity of yet another recurrence and
the need for additional aggressive surgical intervention [20]. For patients with locally
unresectable tumors, another option would be palliative radiation alone. In a case of a
patient with high-grade tumor recurrence that could not be excised, radiation
treatment resulted in local control for 84 months after recurrence [14]. There are no
prospective randomized trial data regarding the best treatment for recurrent phyllodes
tumors.
Metastatic disease Metastatic disease has been reported in 13 to 40 percent of
patients. [1,2,4,18]. Metastases most frequently involve the lungs. After the
development of metastases, mean overall survival is 30 months [48].
As with other soft tissue sarcomas, pulmonary resection is often indicated when
feasible. (See "Surgical treatment and other localized therapy for metastatic soft tissue
sarcoma".)
For patients with unresectable disease, chemotherapy is based upon treatment
guidelines for soft tissue sarcoma [4,49]. The regimen typically consists of
doxorubicin and/or ifosfamide, or a combination of gemcitabine and docetaxel.

Ifosfamide appears to be a particularly active agent, with two of four patients

achieving a complete response in one report [49]. Others suggest benefit with
cisplatin plus either etoposide [44] or doxorubicin [47]. (See "Adjuvant and
neoadjuvant chemotherapy for soft tissue sarcoma of the extremities".)
SURVEILLANCE AFTER THERAPY Given the small number of patients with
malignant phyllodes tumors of the breast, there are no evidence based
recommendations for surveillance after therapy [50,51]. Follow-up guidelines are
adapted from those for soft tissue sarcoma. (See "Local treatment for primary soft
tissue sarcoma of the extremities and chest wall", section on 'Posttreatment cancer
surveillance'.)
Most recurrences occur in the first two years after treatment [37] and most frequently
involve the lungs. Since isolated limited metastatic tumor to the lung is often
asymptomatic and amenable to resection, we follow patients closely for at least two
years:

History and physical examination and chest x-ray every six months for two
years, then annually. If suspicious findings are found on breast examination,
mammography with focused ultrasound and/or MRI of the breast is useful for
evaluation.
Patients who have had breast conservation should resume surveillance with
mammography annually. If suspicious findings are found on mammography,
focused ultrasound and/or MRI is useful for evaluation.
For patients at higher risk for metastatic disease (eg, tumors >5 cm),
surveillance may be performed more frequently. In addition, these high risk
patients are followed with chest CT scans every six months for two years, and
then annually.

SUMMARY AND RECOMMENDATIONS

Phyllodes tumors are uncommon fibroepithelial breast tumors that are capable
of a diverse range of biologic behavior. (See 'Introduction' above.)
Most phyllodes tumors present as smooth, multinodular, painless breast lumps.
While they can be confused with fibroadenomas, suspicion for a phyllodes
tumor should be increased with large tumor size and rapid growth. (See
'Clinical presentation and diagnosis' above.)
The typical appearance of a phyllodes tumor on mammography is a smooth,
polylobulated mass. On ultrasound examination, these lesions are solid,
hypoechoic and, well circumscribed. The presence of cystic areas within the
mass may increase the level of suspicion for phyllodes tumors. (See 'Clinical
presentation and diagnosis' above.)
A core biopsy of a suspicious mass should be performed. Fine needle
aspiration is not a sufficient diagnostic test. If the results are indeterminate,
excisional biopsy should be completed. (See 'Clinical presentation and
diagnosis' above.)
Histologically, phyllodes tumors are classified as benign, borderline or
malignant. (See 'Pathology' above.)
We recommend wide local excision, with a margin of at least 1 cm for
phyllodes tumors as opposed to enucleation or local excision alone (Grade

1B). Recurrence rates are unacceptably high following either local excision or
enucleation without adequate margins. Breast conservation does not
compromise cancer-specific survival. Mastectomy can be reserved for cases
where breast conservation cannot be achieved with an acceptable cosmetic
result. (See 'Treatment' above.)
We suggest not performing axillary dissection for phyllodes tumors (Grade
1C). Axillary lymph node involvement is rarely reported, even with malignant
tumors. (See 'Treatment' above.)
We suggest not performing adjuvant radiotherapy for benign phyllodes tumors
that are widely excised (Grade 1C). (See 'Chemotherapy' above.)
We suggest adjuvant radiotherapy for borderline or malignant phyllodes
tumors (Grade 2C). Radiation substantially reduces the recurrence rate of
these tumors, particularly if it is not possible to obtain a wide margin of 1 cm
of resection. (See 'Treatment' above.)
We suggest that adjuvant chemotherapy should be reserved for patients with
large, high-risk or recurrent malignant tumors (Grade 2C). (See 'Treatment'
above.)
We recommend that hormonal therapy not be used for phyllodes tumors
(Grade 1C). (See 'Treatment' above.)

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