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Nonepithelial Malignancies of the Breast

Nonepithelial Malignancies of the Breast

ABSTRACT: Primary nonepithelial malignancies of the breast comprise an important minority of breast neoplasms, including primary breast sarcomas, therapy-related breast sarcomas, the phyllodes tumors, and primary breast lymphomas. With widespread mammographic detection of breast lesions, these tumors represent critical elements of the differential diagnosis of even benign-appearing lesions. Each has a distinct clinical profile, including presentation, available therapeutic options, and prognosis, further underscoring the importance of timely recognition. The increasing incidence of breast carcinomas and the subsequent therapy thereof may be contributing to an increase in the number of therapy-related breast tumors. This review discusses various features of these uncommon malignancies and their treatment, with the goal of increasing understanding of their clinical behavior and management.

Although much is known about
breast tumors arising from epithelial
tissue, nonepithelial
malignancies remain poorly understood.
Nonepithelial malignancies are
thought to comprise less than 5% of
all breast neoplasms.[1] As such, most
reported series are small with limited
follow-up data. Various institutions
utilize disparate classification schemes
obscuring true prevalence and clinical
course. For example, some categorize
the phyllodes tumor as a
sarcoma, others as a benign lesion,
and still others as an entirely separate
entity.[2,3] Evidence suggests that
treatment of breast carcinoma itself
may be associated with the development
of nonepithelial breast neoplasms.[
4-8] The presentation, patient
demographics, and clinical features
of nonepithelial breast malignancies
mimic those of benign breast neoplasms
or carcinomas in many ways.
Thus, it is important to be able to
distinguish the nonepithelial malignancies
from epithelial breast tumors,
as both prognosis and therapeutic options
differ dramatically.

Nonepithelial tumors of the breast
can be divided into four main categories:
primary breast sarcomas, secondary
or therapy-related breast sarcomas,
phyllodes tumors, and primary breast
lymphomas (see Table 1).[9] Each differs
in presentation, clinical course,
and therapeutic options. Angiosarcomas
are a unique subtype of both primary
and secondary breast sarcomas
that will be discussed separately. The
purpose of this review is to summarize
some of the more recent studies
of each of these uncommon malignancies
in hopes of clarifying the confusion
regarding their prevalence, classification,
natural history, and various
treatment modalities.

Primary Breast Sarcomas

Primary breast sarcomas are malignant
tumors arising from the connective
tissue within the breast. This rare,
heterogeneous group of tumors accounts
for less than 1% of all breast
malignancies.[10] From data compiled
by the Surveillance, Epidemiology,
and End Results (SEER) program of
the National Cancer Institute, the annual
incidence of breast sarcomas has
been reported as 44.8 new cases per
10 million women.[11] The majority
of cases have no known cause.[12]
Established etiologies for breast sarcomas
include prior cancer therapy
such as radiotherapy and the resultant
lymphedema, which will be discussed
below.[4-8,13,14] Breast prostheses
have previously been implicated, but
no association between breast augmentation
and breast sarcomas has
been proven.[11]

Predisposing factors for sarcomas
in other locations likely apply to breast
sarcomas as well. These include genetic
syndromes such as Li-Fraumeni
syndrome, Gardner's syndrome, and
neurofibromatosis type 1.[15] Environmental
associations include chemotherapeutic
agents (eg, alkylating
agents), arsenic compounds, vinyl
chloride, immunosuppressive agents,
human immunodeficiency virus, and
human herpesvirus type 8.[15]

Primary breast sarcomas most often
present as large, painless breast lumps.
They are seldom associated with skin
and nipple changes or axillary lymphadenopathy.[
2,16,17] Clinically, these tumors
often exhibit more rapid growth
than epithelial malignancies or benign
lesions.[17] The tumor size can be
quite large (median: 5.8 cm, range:
1.5-30 cm).[10,16] The typical patient
is a woman in her 5th decade of life
(range: 17-89 years); however, primary
breast sarcomas have also been
reported in men.[3,10,16]

Pathology and Histology
The mammographic appearance of
primary breast sarcomas varies with
the histologic subtype. In general, they
lack calcification and spiculation and
may be mistaken for benign breast lesions
such as fibroadenomas.[12] For
this reason, in addition to a pathologic
diagnosis, historical features such as
rapid growth and imaging modalities
such as fluorodeoxyglucose-positronemission
tomography scanning may
be useful in distinguishing malignant
breast sarcomas from benign breast
lesions.[2] Incisional, excisional, and
core-needle biopsies are all useful in
arriving at a definitive diagnosis. Although
fine-needle aspiration can be
diagnostic, it does not allow for determination
of subtype or grade.

The histologic types of primary
breast sarcomas vary widely. Evaluation
of subtype distribution is limited
not only by the rarity of the disease,
but also by differences in the classification
of sarcomas. In one series of
90 patients with primary breast sarcomas
(excluding cystosarcoma phyllodes)
treated at the Institut Gustave-
Roussy, the histologic types included
malignant fibrous histiocytoma
(69.5%), angiosarcoma (10%), liposarcoma
(8%), malignant peripheral
nerve sheath tumor (2.5%), spindlecell
sarcoma (2.5%), extraskeletal osteosarcoma
(2.5%), rhabdomyosarcoma
(2.5%), and leiomyosarcoma
(2.5%).[16] Another single-institution
series included subtype descriptions
for 78 patients with breast sarcomas.
Their reported histologic types included
malignant cystosarcoma phyllodes
(55%), stromal sarcomas (24%),
angiosarcomas (14%), fibrosarcomas
(12%), liposarcomas (7%), and others
(21%).[10]

Given the differences in classification,
an accurate determination of the
distribution of primary breast sarcomas
remains challenging. In general,
malignant fibrous histiocytomas, fibrosarcomas,
liposarcomas, and angiosarcomas
comprise the major subtypes
of breast sarcomas.

Prognostic Factors
The prognosis for primary breast
sarcomas is based on the characteristics
of soft-tissue sarcomas elsewhere
in the body and primarily on the histologic
grade and size of the tumor.[
3,10,16] Tumor grade is an important
prognostic factor in most
sarcomas, and therefore constitutes the
foremost variable in the staging system
of primary breast sarcomas (see
Table 2). Pathologic features used to
define grade generally include differentiation,
the mitotic count, necrosis,
cellularity, and pleomorphism.[18]

The French series of 90 patients
with grade 1, 2, and 3 breast sarcomas
had corresponding 10-year overall
survival rates of 82%, 62%, and 36%,
respectively (P = .00007). Size was
also an important prognostic factor in
this series. The 10-year overall survival
rates for tumors < 5 cm, 5 to
10 cm, and > 10 cm on univariate
analysis were 76%, 68%, and 28%, respectively
(P = .002).[16] However,
multivariate analysis did not corroborate
the association in this or other
studies.[3,16] Other factors such as
age, number of mitoses, menopausal
status, history of benign breast disease,
and initial therapy have not been
shown to significantly affect outcome.[
3,10,16] The only subtype that
may confer a poor prognosis is
angiosarcoma.[16]

Primary breast sarcomas tend to
spread locally or hematogenously and
are not typically associated with regional
lymph node involvement. Even
when palpable axillary lymphadenopathy
is present, pathologic exami-
nation often fails to reveal disease
spread.[3] However, metastatic disease
to the lymph nodes has been reported.
McGowan and colleagues reported
that two of three patients with carcinosarcomas
who underwent axillary
lymph node dissections were found to
have nodal metastases. Notably, only
epithelial components were present in
the lymph nodes.[10] We believe that
carcinosarcomas actually represent a
poorly differentiated carcinoma, rather
than a sarcoma. Liposarcomas have
also been noted to have up to a 10%
incidence of nodal involvement.[2] In
addition, lymph node involvement has
been implicated in cases of widespread
disease, which can be considered more
akin to metastatic than regional
spread.[2]

Treatment Recommendations

  • Surgery-Given the rarity of
    breast sarcomas, no prospective randomized
    trials have evaluated potential
    therapies. Because the behavior,
    histology, and prognosis of primary
    breast sarcomas are similar to that of
    other soft-tissue sarcomas, therapeutic
    recommendations are based on data
    from the latter setting. Results of retrospective
    analyses on outcomes related
    to therapy for breast sarcoma
    also aid in management. As with all
    soft-tissue sarcomas, a multidisciplinary
    approach at an experienced
    center involving the surgical oncologist,
    radiation oncologist, and medical
    oncologist is necessary.[19]
    Tumors are then treated according to
    both histologic grade and size. Surgery
    remains the mainstay of therapy.

    The type and extent of surgery
    should be based on feasibility and the
    size of the tumor and breast. Retrospective
    studies have shown no
    statistically significant difference in
    cause-specific survival with breastconserving
    surgery vs mastectomy, if
    negative margins are achieved.[10]
    Given the lack of multicentricity of the
    majority of primary breast sarcomas,
    wide local excision should be adequate.[
    16,12] An adequate resection
    margin is the single most important
    determinant of long-term survival.[20]
    In cases of local recurrence, salvage
    mastectomy may be effective.[16] Due
    to the natural history of breast sarcomas,
    axillary dissection is rarely necessary,
    but it may be considered in
    cases of palpable lymphadenopathy,
    carcinosarcoma, or liposarcoma.[2,10]

  • Radiotherapy-Adjuvant radiotherapy
    is still controversial due to
    conflicting data from small retrospective
    studies.[10,12,21,22] Johnstone
    and colleagues reported a case series
    of 10 patients treated with mastectomy
    and adjuvant radiation who
    experienced no local or regional failures.[
    21] Other studies have suggested
    that radiation does not improve
    disease-free survival but that it may be
    useful in the treatment of high-grade
    but not low-grade lesions.[16,12]

    Given the retrospective nature of
    these reports and the attendant confounding
    factors, it is helpful to examine
    the larger pool of experience
    with sarcomas in general. In prospective
    studies of radiation plus surgery
    for lower-extremity sarcomas, adjuvant
    radiation is associated with a significant
    improvement in local control
    of both low- and high-grade tumors
    but without improvement in overall
    survival.[23] Adjuvant radiation is
    also likely to be of some benefit, especially
    in the setting of breast-conserving
    therapy and high-grade or
    large tumors.

    Because radiotherapy of the breast
    may be associated with occasional
    quality-of-life and rare life-threatening
    consequences (see below), a thor-
    ough evaluation of the risks of adjuvant
    radiation therapy should be made
    depending on the individual patient and
    malignancy. The emphasis should be on
    treating tumors with questionable or
    positive margins, high-grade features,
    and those that are larger in size.

  • Chemotherapy-Adjuvant chemotherapy
    does not have a clearly
    defined role in the treatment of primary
    breast or soft-tissue sarcomas.
    A meta-analysis by the Cochrane Collaborative
    evaluated 14 trials involving
    a total of 1,568 adults with
    resectable soft-tissue sarcoma randomized
    to adjuvant chemotherapy or
    no chemotherapy following local therapy.
    The hazard ratio for recurrencefree
    survival with chemotherapy was
    0.75 (P = .0001). No significant benefit
    in overall survival was associated
    with adjuvant chemotherapy, but a
    possible trend for improvement was
    noted. Subgroup analysis revealed that
    the best overall survival was associated
    with extremity lesions (hazard ratio
    = 0.8, P = .029).[24]

    A subsequent Italian study of intensified
    adjuvant chemotherapy, limited
    to adult soft-tissue sarcomas of the
    extremities and pelvis, revealed a significant
    benefit in median overall survival
    for treated vs untreated patients
    (75 vs 46 months, P = .03).[25]

    Although primary breast sarcomas
    have not been studied exclusively, data
    from studies regarding sarcomas in
    general suggest there may be a role
    for adjuvant chemotherapy in patients
    with high-grade and large tumors, ideally
    in the setting of a clinical trial.[26]
    Some active agents for sarcoma
    include doxorubicin, epirubicin
    (Ellence), and ifosfamide (Ifex) or
    combination chemotherapy regimens
    such as MAID (mesna [Mesnex],
    doxorubicin [Adriamycin], ifosfamide,
    dacarbazine [DTIC-Dome]) or MAP
    (mitomycin [Mutamycin], doxorubicin,
    cisplatin [Platinol]).[25,27,28]
    Gemcitabine (Gemzar) has been
    shown to have limited activity against
    soft-tissue sarcomas, especially in a
    salvage situation.[29] The combination
    of gemcitabine and docetaxel
    (Taxotere) has shown early promise;
    however, further investigation is
    necessary.[30,31]

Therapy-Related
Breast Sarcomas

It is estimated that in 2004, over
200,000 women in the United States
will be diagnosed with breast carcinoma,
and approximately 40,000 will
die of the disease.[32] With an increasing
incidence and subsequent treatment
of these lesions, concern is growing
about the incidence of therapyrelated
breast tumors. Secondary malignancies
as a result of breast cancer
treatment are well-documented but
remain relatively rare, and although
therapy-related breast sarcomas are
most frequently sequelae of breast carcinoma
treatment, they are also associated
with the treatment of other malignancies
that involve the breast in the
radiation field.[6]

Several variables make it difficult
to estimate the true incidence of
therapy-related sarcomas, and it is
possible that the incidence of these
tumors is underestimated. For example,
in patients with a history of
breast carcinoma, new lesions may be
presumed to be local recurrences or
metastatic disease.[4] Another complicating
issue is that some patients may
be predisposed to multiple primary
malignancies, which may include both
breast carcinoma and sarcoma.

Li-Fraumeni syndrome is an autosomal
dominant disorder in which
there is a germ-line mutation in the
p53 tumor-suppressor gene. Patients
with this syndrome are susceptible to
developing multiple malignancies-
including sarcomas, leukemias, and
bilateral breast, brain, lung, adrenal,
and laryngeal cancer-at a relatively
young age.[33] This is just one condition
in which breast carcinoma and
sarcoma may coexist as a result of
causes not related to therapy. Heretofore
undescribed syndromes may
exist in which multiple breast neoplasms
coexist.

The Radiotherapy Factor
The risk of developing soft-tissue
sarcomas after breast cancer is highest
when treatment involves radiotherapy.
Ionizing radiation is a known
carcinogen that can induce sarcoma.[
6,13] Axillary radiation-induced
lymph node sclerosis and resultant
lymphedema is another possible
mechanism for radiation-related tumors
(see Mammary Angiosarcomas).
A correlation may also exist between
the integral dose of radiation and the
development of a sarcoma in the radiation
field.[4]

The possible effects of radiation
therapy are reported in numerous
population-based studies of patients
treated for breast carcinomas. In one
large series of 274,572 breast cancer
patients identified in SEER registries,
the incidence of new cases of sarcoma
at 15 years posttreatment among those
receiving radiation therapy was 3.2 per
1,000, compared to 2.3 per 1,000
among those not receiving radiation
(P = .001).[12] Another retrospective
study reported the relative risk of
breast sarcoma as 2.2 (95% confidence
interval [CI] = 1.4-3.3) for breast cancer
patients who received radiotherapy
compared to those who did not.[8]

In contrast, Obedian and colleagues
did not find an excess of subsequent
malignancies in 1,029 breast cancer
patients who underwent lumpectomy
and radiation therapy, compared to
1,387 patients treated with mastectomy.[
34] However, given the rarity of
sarcomas (only seven were diagnosed
in this trial), it may be difficult to detect
a difference in this particular subgroup.

Histopathology and
Treatment Protocols

Patients with therapy-related breast
sarcomas are usually women in their
6th or 7th decades who have been
treated for breast carcinomas approximately
11 years (range: 3-44 years)
earlier.[5-7] Mean tumor size at diagnosis
is 4.2 cm.[7] The tumors can
present similarly to primary breast
sarcomas. However, they may be more
difficult to detect on physical examination
or mammogram, as abnormalities
of the breast or mastectomy
site are often attributed to postirradiation
changes.

The histopathology of these tumors
includes a wide range of soft-tissue
sarcomas, with proportions that vary
significantly depending on the series.
The most frequently reported subtypes
include leiomyosarcomas, malignant
fibrous histiocytomas, liposarcomas,
fibrosarcomas, and angiosarco
mas.[13] Compared with other tumors,
angiosarcomas appear to occur more
frequently in patients who have had
prior therapy.[4,5,8,13]

Similar to primary breast sarcomas,
prognosis correlates with tumor
grade.[6] The overall prognosis in
breast cancer patients after diagnosis
of sarcoma is generally poor, with a
reported median survival of 2.3 years
and 5-year survival rates of 27% to
35%.[5,8,13]

The cornerstone of therapy continues
to be surgery, although outcomes
remain poor due to local aggressiveness.
Operative procedures are often
difficult, as the sarcomas arise in irradiated
areas.[6] In a report of 15 patients
who underwent radical resection
of radiation-induced chest wall sarcomas,
3 patients suffered complications
of surgery, 7 had local recurrences, and
4 died of metastatic disease.[35] Radiotherapy
has also been used with
little success, as these tumors tend to
be radiation-resistant.[6] There are
also limits to the amount of additional
therapy that may be given in previously
irradiated areas, and chemotherapeutic
options are limited as well.

The indisputable benefit of radiation
therapy in the treatment of breast
carcinoma would still appear to outweigh
the small risk of sarcoma after
therapy.[8] Moreover, available data
regarding the relationship of radiation
and sarcomas are gathered from retrospective
studies that span back many
decades. Significant technical advances
have since been made in radiation
oncology and may serve to lower
the reported incidence rate even further.
Some retrospective studies include
sarcomas developing outside the
radiation field for breast cancer
therapy, which casts further doubt on
the causality of radiotherapy. Nevertheless,
one must be cognizant of the
increased risk of this rare tumor for
purposes of early detection, patient
counseling, and treatment.

Mammary Angiosarcomas

Angiosarcomas are aggressive, heterogeneous
malignancies that arise
from endothelial cells. These tumors
are sometimes referred to separately
as lymphangiosarcomas or hemangiosarcomas
derived from lymphatic
or capillary endothelium, respectively.
As this pathologic distinction can be
quite difficult and is not always clearly
defined, we will refer to both of these
subtypes collectively as angiosarcomas.

The annual incidence of mammary
angiosarcomas has been reported as
5.8 per 10 million women,[11] and
although angiosarcomas in general are
extremely rare, the breast is one of the
more common sites of occurrence.
These malignancies are notable as sequelae
of therapy for breast carcinoma.
Of all sarcomas arising after breast
cancer therapy, many studies report
angiosarcomas as the most common
histologic subtype.[8,13] In a population-
based study in Los Angeles
County, the adjusted relative risk of
developing an angiosarcoma among
women with a prior diagnosis of breast
cancer compared to women without a
prior diagnosis was 59.3 (95% CI =
21.9-152.8).[36] However, this relationship
has not been borne out in all
studies.[37]

Pathogenesis
Therapeutic radiation has been
closely implicated in the pathogenesis
of angiosarcomas (see Therapy-
Related Breast Tumors). In one series
of over 274,000 patients, the mean incidence
at 15 years was 0.9 per 1,000
cases receiving radiation and 0.1 per
1,000 (P = .0001) cases not receiving
radiation.[13] Another series of over
194,000 women with breast carcinoma
demonstrated a relative risk of developing
angiosarcoma of 15.9 (95% CI =
6.6-38.1) for patients treated with radiation
therapy compared to those
treated with other modalities.[8]

A second association in the pathogenesis
of angiosarcomas is lymphedema.
Angiosarcomas can occur in
chronically lymphedematous extremities
from various etiologies.[38]
Stewart and Treves originally described
angiosarcomas (or lymphangiosarcomas)
of the upper extremity,
breast, and axilla arising in women
with chronic lymphedema who had
been previously treated for breast cancer.[
14] This occurrence has since
been designated as Stewart-Treves
syndrome. Lymphedema of the upper
extremity and breast may occur as a
result of surgery (particularly axillary
dissections) or radiation therapy (via
axillary lymph node sclerosis). Thus,
it is difficult to distinguish whether an
angiosarcoma is secondary to lymphedema,
primary radiotherapy, or a combination
thereof.

Clinical Presentation
Mammary angiosarcomas tend to
occur in either young women with no
prior cancer or in older women following
therapy for breast carcinoma.[
11,36] The clinical presentation
is that of a palpable growing breast
mass that may have an overlying bluish
tint to the skin. The age at diagnosis
ranges from 17 to 70 years with a
median age of 38 years, which is
younger than for typical breast carcinomas.[
37] Mammographically, angiosarcomas
can appear ill-defined
without spiculae or calcifications
or may not be apparent at all, even
in patients with large palpable
masses.[2,39] Tumor size ranges from
1 to 15 cm with a median of 5 cm.[40]

Lymphedema-associated angiosarcomas
can appear as single or multiple
purplish macular or papular lesions in
the edematous upper extremity or as a
deeper ecchymoses or cellulitis.[41]
The average age of occurrence is 64
years (range: 44-84 years).[11] In the
Los Angeles study, the mean time from
development of the original breast carcinoma
to subsequent Stewart-Treves
syndrome was 9.7 and 4.4 years for
upper extremity and chest or breast
tumors, respectively.[36]

Prognosis
The single most important indicator
of prognosis for patients with angiosarcomas
is histologic grade. A series
of 32 patients with angiosarcoma
reported 10-year recurrence-free survival
rates of 76%, 70%, and 15% for
patients with grade 1, 2, and 3 tumors.[
40] The natural history of angiosarcomas
is also highly dependent
on tumor grade. Low-grade tumors
follow an indolent course, whereas
high-grade tumors are extremely aggressive.[
42] These angiosarcomas
metastasize early, most often to the
lung and liver. However, they also tend
to metastasize to bones, skin, and the
contralateral breast, which are unusual
locations for other soft-tissue
sarcomas.[40]

Overall survival in angiosarcoma
patients is generally quite poor, with
a median lifespan after diagnosis of
approximately 15 months.[17] With
more aggressive management strategies,
survival rates appear to be improving
in recent years, but further improvement
is required given the poor
prognosis.[43]

Treatment Options
Therapy for angiosarcoma is based
primarily on local control. Surgical
management, ranging from wide local
excision to chest wall resection,
should be chosen to optimize chances
of complete resection and preservation
of form.[42] Despite aggressive surgical
management, local recurrences
are common, and repeat surgery is
often necessary. Radiation therapy
may play a useful role in the neoadjuvant
or adjuvant setting, but few
data exist to support this hypothesis
at present.[42] Similarly, little is
known about the utility of chemotherapeutic
agents, but agents used to treat
other soft-tissue sarcomas may be employed
(see Primary Breast Sarcomas).

In summary, angiosarcomas are
locally aggressive soft-tissue sarcomas
that arise primarily in the breast
and are associated with prior breast
cancer therapy (with or without radiation)
or in the setting of chronic
lymphedema. Prognosis is based on
histologic grade, and therapy is centered
on surgical resection with the
possible addition of radiation. Because
angiosarcomas are composed of
vascular tissue, future therapy may
include vascular-targeting agents or
antiangiogenesis drugs.[42]

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