Những Nguyên Tắc Thiết Yếu Trong Phẫu Thuật Tuyến Vú (Essentials of Breast Surgery)

biopsy of these additional lesions is necessary
because the identification of multicentric disease
would preclude breast conservation therapy
(BCT) after chemotherapy. Likewise, the identifi-
cation of multicentric disease or diffuse calcifica-
tions before chemotherapy should prompt a
discussion with the patient regarding the need
for mastectomy regardless of degree of response
to the chemotherapy. In this way, there are no
surprises or mixed messages, and the patient
has time during the chemotherapy to come to
terms with the need for mastectomy. Likewise,
there may be time for genetic counseling and
testing, and for patients to consider whether
they want the contralateral breast removed for
prophylaxis.
Core biopsy is the optimal method for diag-
nosing LABC because this provides adequate
tissue for immunohistochemistry (IHC) stain-
ing for estrogen receptor (ER), progesterone
receptor (PR), and human epidermal growth
factor receptor 2 (Her-2/neu), which are imper-
ative to make decisions regarding systemic
therapy, which will be the first step. Multiple
cores should be taken to confirm the entire
mass is invasive because occasionally (although
rarely), ductal carcinoma in situ (DCIS) can
present as a large bulky mass. If the core biopsy
is non-diagnostic, negative, or suggests primar-
ily noninvasive disease, the surgeon should
perform an incisional biopsy of the breast for
a more definitive diagnosis. If patients have
skin involvement, a punch biopsy of the
affected skin can also provide the diagnosis.
Because of the high risk of distant disease, all
patients with LABC should undergo a thorough
search for metastatic disease. The incidence of
metastatic disease rises from approximately
2% to 3% for early stage disease to as high as
30% for LABC. The metastatic workup should
include laboratory work, bone scan, and com-
puted tomography (CT) scans of the chest,
abdomen, and pelvis. Positron emission tomo-
graphy (PET) scan is being investigated as a
staging examination, and although it should
not serve as a substitute for these other studies,
it may serve as a useful adjunct. MRI of the brain
is only indicated when central nervous system
symptoms are present. Even with the advanced
nature of their primary disease, the majority of
patients with LABC will have no evidence of
distant disease.
Treatment of Locally Advanced
Breast Cancer
History of Treatment for Locally
Advanced Breast Cancer
Because breast cancer had always been a surgi-
cal disease, surgery was also the primary therapy
for LABC, specifically the radical mastectomy.
Haagensen and Stout first reported the ex-
tremely poor outcomes associated with this
approach, with high local recurrence rates and
poor survival. It was this experience on which
early staging systems for breast cancer were
based, identifying poor candidates for surgery
as those with extensive breast skin edema, satel-
litosis, intercostal/parasternal nodules, lymph-
edema of the arm, supraclavicular metastases,
or IBC. Patients with ulceration, limited skin
edema, fixation, or bulky adenopathy were
not necessarily considered inoperable, but as
having a poor prognosis.
Given
the
limitations
of
surgery
in
controlling LABC, the potential of radiation
was examined, but likewise yielded poor local
control and had minimal impact on survival.
A combination of radiation and surgery failed
to improve disease control. It was not until
the introduction of preoperative chemother-
apy that improvements in the outcome of
patients with LABC were realized. When first
proposed, surgeons were hesitant to deliver
chemotherapy
before
surgery,
worried
not
only about an increase in surgical complica-
tions but also a negative impact on survival
secondary to delaying the operation. However,
several series not only showed that the opera-
tive morbidity was not worse, but also showed
that it may actually improve tumor downsta-
ging. And in contrast to concerns that preoper-
ative treatment and deferral of surgery may
increase rates of unresectability, approximately
80%
of
patients
will
have
at
least
50%
Figure 19–1. Locally advanced breast cancer.
291
19—LOCALLY ADVANCED AND INFLAMMATORY BREAST CANCER

shrinkage of the primary tumor mass, and only
2% to 3% will have signs of progressive disease.
More importantly, both local control rates
and survival improved significantly with the
introduction of preoperative chemotherapy for
LABC.
Induction Chemotherapy
Today, the treatment of LABC will be multi-
modality, beginning with systemic chemother-
apy. Not only will this provide early treatment
of the micrometastases that are highly likely to
be present, but also downstaging the primary
and regional disease will facilitate surgery.
In the setting of LABC, the preoperative che-
motherapy is often referred to as induction
chemotherapy or neoadjuvant chemotherapy.
Induction chemotherapy is a better term because
it differentiates the mandatory therapy used in
LABC from the optional neoadjuvant chemo-
therapy used when mastectomy is feasible;
however, tumor downstaging may allow for
breast conservation. The use of the term neoad-
juvant chemotherapy for both clinical situations
sometimes confuses students and residents
into thinking the chemotherapy for LABC is
optional.
Although there is no standard regimen for
the induction chemotherapy in LABC, the
most aggressive regimens are typically chosen.
Adriamycin, cytoxan, and a taxane is the most
common regimen used. Several trials have
demonstrated the benefit of adding a taxane,
particularly docetaxel, in patients with LABC.
If the patient is Her-2/neu positive, Herceptin
should be considered, given the increased
response rate associated with it.
During chemotherapy, the patient should
have periodic assessments of their response,
including not only physical examination, but
also after one or two cycles, repeat imaging
with breast ultrasound or mammogram. Other
imaging modalities such as MRI, PET, and
sestamibi nuclear medicine studies have been
examined as methods of monitoring response
to induction chemotherapy, but they are still
considered experimental. If no clinical response
is noted, repeat biopsies of the lesion may also
help determine if there is a pathologic tumor
response. If no clinical or pathologic response
is noted, or worse, if the disease progresses, a
decision should be made to either abandon
systemic therapy and move to surgery or switch
to a different systemic regimen. This will require
a multidisciplinary assessment to determine
whether the patient is presently resectable or
the likelihood of a different regimen working.
Local Surgery after Induction
Chemotherapy
After the completion of induction chemother-
apy, the patient will return to the surgeon.
Most patients will be ready to undergo surgery
approximately 3 weeks after the last chemo-
therapy treatment, when the absolute neutro-
phil and platelet counts have normalized
(greater than 1500 and 100,000, respectively).
For most patients, this means a mastectomy.
Breast conservation is an option, but this will
depend on the stage of their cancer after che-
motherapy. Researchers at the MD Anderson
Cancer Center retrospectively studied their
LABC population to determine the optimal
candidates for BCT. They recommended that
patients only be considered for breast conser-
vation if they met certain criteria (Box 19–1).
As with all patients with breast cancer, the
patients must be desirous of breast conserva-
tion, have no contraindications to radiation,
and not have multicentric disease or wide-
spread calcifications on mammography. In
their series, the pretreatment size was not as
strong a predictor of local recurrence as the
posttreament size. Patients with clinical N2 or
N3 disease
before chemotherapy
do
have
higher rates of local failure, but this is true
for both BCT and mastectomy and is not a
contraindication to lumpectomy.
Many patients are desirous of immediate
reconstruction
after
mastectomy.
However,
BOX 19–1 CONTRAINDICATIONS
TO BREAST CONSERVATION
SURGERY AFTER INDUCTION
CHEMOTHERAPY FOR LOCALLY
ADVANCED BREAST CANCER
Before Chemotherapy


Multicentric disease


Extensive suspicious microcalcifications


Contraindication to radiation therapy


Extensive intramammary lymphatic
invasion


Inflammatory breast cancer
After Chemotherapy


Skin edema has not completely resolved


Residual tumor >5 cm (or still too large
for reasonable cosmetic outcome)
292
SURGICAL FOUNDATIONS: ESSENTIALS OF BREAST SURGERY

most of these patients will be recommended to
undergo postmastectomy radiation. Radiating
tissue expanders and implants results in a high
rate of complications and is generally discour-
aged (see Chapter 14). In addition, recent
studies have demonstrated excessive rates of
cosmetic complications following irradiation
of autogenous tissue reconstructions, but occur-
ring in a delayed fashion. The decision to pro-
ceed with immediate breast reconstruction in
patients with known LABC should be made
cautiously, and implant reconstructions should
be avoided whenever postmastectomy radiation
is planned. Occasionally, patients with LABC
will require plastic surgery at the time of mas-
tectomy purely for soft tissue coverage of an
extensive chest wall defect. In these cases the
latissimus dorsi flap is the most frequently
used approach because this flap is a relatively
straightforward procedure technically, and it
provides durable, radiation-tolerant chest wall
coverage.
Regional Surgery after Induction
Chemotherapy
The majority of patients with LABC will pres-
ent with regional metastases. With the routine
use of axillary ultrasound and ultrasound
guided FNA biopsy, most of these patients will
have documented disease in their regional
nodes before induction chemotherapy. At the
completion of induction chemotherapy, axil-
lary lymph node dissection (ALND) should
be performed at the time of either their mas-
tectomy
(modified
radical
mastectomy)
or
lumpectomy.
With the introduction of sentinel lymph
node (SLN) biopsy, several researchers have pro-
posed using SLN biopsy after induction chemo-
therapy as a method of sparing women who
were downstaged to N0 disease from the mor-
bidity of ALND (see Chapter 13). Approximately
20% of patients may be converted from node
positive to node negative. This approach pre-
sumes that SLN biopsy will work after induction
chemotherapy. There have been concerns that
lymphatic pathways may have been altered by
either the disease or by the chemotherapy, lead-
ing to increased false-negative rates. Series of
SLN biopsy followed by ALND in patients
receiving
neoadjuvant
chemotherapy
have
been variable, with some suggesting an unac-
ceptably high false-negative rate, and others
suggesting accuracy similar to SLN biopsy in
operable breast cancer. Although SLN biopsy
after chemotherapy appears to be safe, the
patients in these trials were primarily patients
with operable breast cancer undergoing neoad-
juvant chemotherapy. There is little data regard-
ing the safety of SLN biopsy specifically after
induction chemotherapy for LABC. Further
research is necessary before this can be recom-
mended, although it may be an option for
selected patients (Box 19–2).
Inflammatory Breast Cancer
A much more aggressive form of LABC is IBC,
with 5-year survival rates of only 15%. IBC is a
discrete form of breast cancer, and although
neglected LABC may develop inflammatory
changes, primary IBC is a distinct entity.
Although it only accounts for 1% to 5% of
breast cancers in the United States, it has a
much more significant impact on mortality.
The incidence varies with geography and
is considerably higher in areas such as the
mid-East and northern Africa. The median
age at diagnosis is slightly younger than for
non-IBC.
Women present with a red discoloration of a
large portion of the breast. The involved area is
warm to the touch, edematous, and has dim-
pling of the overlying skin, known as peau
BOX 19–2 TREATMENT SUMMARY
FOR LOCALLY ADVANCED BREAST
CANCER
1.
Diagnosis by physical examination,
breast imaging, and core biopsy.
2.
Complete staging for distant metastases
(computed tomography, bone scan).
3.
Consider sentinel node biopsy for
patients who are clinically node negative.
4.
Induction chemotherapy, typically four
cycles of doxorubicin and
cyclophosphamide (AC) followed by
four cycles of a taxane (paclitaxel or
docetaxel). Inclusion of Herceptin for
patients who are positive for Her-2/neu.
5.
Surgery. Lumpectomy and axillary
lymph node dissection (ALND) versus
modified radical mastectomy. For
patients determined to be sentinel
lymph node (SLN) negative before
chemotherapy, ALND may be omitted.
SLN after chemotherapy is controversial.
6.
Radiation therapy.
7.
Hormone therapy for patients who are
hormone-receptor positive.
293
19—LOCALLY ADVANCED AND INFLAMMATORY BREAST CANCER

d’orange (orange peel skin; Fig. 19–2). Physical
examination often shows palpable adenopa-
thy (approximately in one third of patients,
although almost all patients with have patho-
logic involvement). Often the axillary lymph
nodes are matted. The most striking aspect of
IBC is that these changes tend to come up
rather quickly, over the course of a few weeks.
It is not, therefore, difficult to imagine how
most physicians who initially see IBC would
think these changes were related to infection
rather than malignancy.
Diagnosis and Workup
Because mastitis is more common than IBC, it
is not unusual for the first physician to see the
patient to start the patient on a course of anti-
biotics. However, in the patient who has the
rapid onset of these symptoms without a clear
initiating factor for infection (trauma, recent
breast-feeding, etc.), a high suspicion of IBC
must be entertained and biopsy obtained
early. In addition, patients with IBC do not
have the fever and elevated white blood cell
count that women with mastitis have. Biopsy
should also be performed immediately in a
patient with inflammatory changes who does
not rapidly respond to antibiotics. Antibiotics
tend to be of immediate benefit in mastitis.
Sometimes in a woman with IBC, a slight
decrease in the erythema will be seen with
antibiotics, without complete resolution, lead-
ing the physician to incorrectly conclude this
is infectious and leading to several trials of dif-
ferent antibiotics. Several weeks go by before
a biopsy is performed, and this delay in
diagnosis can be devastating for the patient.
Sometimes IBC may be confused for skin
problems such as atopic dermatitis, psoriasis,
eczema, or vasculitis, and steroids are initiated
before obtaining a biopsy. Again there may be
a minimal response that leads to an incorrect
diagnosis, whereas a skin biopsy would con-
firm the diagnosis and avoid a delay in initiat-
ing therapy for IBC.
For any patient suspected to have IBC, a
core-needle biopsy should be obtained of any
palpable mass; however, there is often no pal-
pable abnormality except for some induration
of the involved area. A skin biopsy should also
be obtained. The classic histologic finding of
IBC is dermal lymphatic invasion by tumor
cells. These tumor emboli obstruct lymphatic
drainage, leading to the clinical manifestations
of IBC. If palpable adenopathy is present, FNA
biopsy may also help secure the diagnosis.
Dermal lymphatic invasion will be present in
about 75% of cases, but its absence does not
rule out IBC; the diagnosis can be made on
clinical assessment only.
Mammography and directed breast ultra-
sound should be obtained to document the
presence of any underlying abnormalities and
provide a baseline to compare to when trying
to assess response. However, biopsy should
not be delayed until the breast imaging is
obtained; it should be done immediately on
seeing the physical changes suspicious for
IBC. Mammography will often demonstrate a
mass or thickening in the breast. In addition
there are other signs of inflammation in the
breast, such as skin thickening and stromal
coarsening (Fig. 19–3).
Once IBC is diagnosed, the patient should
have a full staging workup, including a thor-
ough history and physical, CT scan of the
chest/abdomen/pelvis, and bone scan. Further
imaging studies should be directed by the pres-
ence of symptoms.
It should also be mentioned that sometimes
a primary breast cancer, treated by lumpec-
tomy and radiation therapy, can recur with
inflammatory features. Biopsy of the skin will
show widespread invasion of the cancer into
the dermis and epidermis. Although this is
not true IBC, it does require immediate inter-
vention. Often this inflammatory recurrence
is misdiagnosed as a postoperative infection
or lymphedema of the breast following radi-
ation therapy. If the condition fails to resolve
with antibiotics or other interventions, biopsy
should be performed sooner rather than later.
Figure 19–2. Inflammatory breast cancer showing
the classic finding of peau d’orange. (Image courtesy
of Dr. Tara Breslin, Department of Surgery, Univer-
sity of Michigan).
294
SURGICAL FOUNDATIONS: ESSENTIALS OF BREAST SURGERY

Treatment of Inflammatory Breast
Cancer
The treatment of IBC is multimodality: neoad-
juvant chemotherapy followed by surgery (if
the patient becomes resectable) followed by
radiation therapy (Box 19–3). This is followed
by hormonal therapy in patients with hor-
mone-receptor-positive disease, although IBC
is more commonly ER/PR negative than non-
IBC. Patients treated by all three modalities
have
significantly
improved
survival
over
patients treated with radiation alone, chemo-
therapy alone, surgery plus radiation, or radia-
tion plus chemotherapy. Several studies have
examined whether mastectomy is necessary,
looking instead at chemotherapy followed by
radiation only. Although some studies found
no difference in either disease-free or overall
survival, others found a significant benefit to
local-regional control with the mastectomy
and a possible impact on overall survival.
Therefore there is no reason to exclude surgery
in suitable candidates. In addition, there are
other advantages to surgery as part of the mul-
timodality treatment of IBC. Surgery provides
important prognostic information regarding
the pathologic response to the chemotherapy.
The clinical response rate (based on physical
examination and mammography) does not
accurately reflect the pathologic response rate,
and this information is useful in deciding
whether additional chemotherapy after radia-
tion therapy may be of use. In addition, sur-
gery provides prompt control of bulky tumor
burden and may allow for a lower dose of radi-
ation therapy to be delivered to the chest wall.
Surgery for IBC consists of a modified radical
mastectomy. Nodal involvement is present in
almost all cases, and the accuracy of SLN
biopsy after neoadjuvant chemotherapy for
IBC appears poor. Although there have been
some reports of using breast conservation in
patients who have a complete or nearly com-
plete pathologic response, the body of evi-
dence
is
minimal
compared
to
that
for
neoadjuvant chemotherapy for T1 through
T3 tumors (or even LABC), and it is difficult
to predict what the local recurrence rate would
be. Breast conservation is therefore strongly
discouraged and should only be considered
for highly selected patients in whom a com-
plete pathologic response has been clearly
demonstrated. Even then, it is best restricted
to research protocols.
BOX 19–3 TREATMENT SUMMARY
FOR INFLAMMATORY BREAST
CANCER
1.
Diagnosis by physical examination,
breast imaging, core biopsy, and punch
biopsy of skin.
2.
Complete staging for distant metastases
(computed tomography, bone scan).
3.
Induction chemotherapy, typically four
cycles of doxorubicin and
cyclophosphamide (AC) followed by
four cycles of a taxane (paclitaxel or
docetaxel). Inclusion of Herceptin for
patients who are positive for Her-2/neu.
4.
Modified radical mastectomy
5.
Chest wall radiation.
6.
Hormone therapy for patients who are
hormone-receptor positive.
Figure 19–3. Right
MLO view demonstrates skin
thickening. A 32-cm area of focal asymmetry is seen
in the superior breast. Core-needle biopsy of breast
demonstrated invasive ductal carcinoma. Skin punch
biopsy demonstrated tumor in the dermal lympha-
tics. Findings are consistent with inflammatory breast
carcinoma. (Image courtesy of Dr. Alexis Nees,
Department of Radiology, University of Michigan).
295
19—LOCALLY ADVANCED AND INFLAMMATORY BREAST CANCER

Mastectomy should be followed by postmas-
tectomy radiation therapy, even in patients
who had a complete pathologic response.
Local-regional failures are significantly lower
in patients who receive modified radical mas-
tectomy and electron beam therapy compared
to electron beam therapy alone. Although the
exact impact this has on overall survival is
unknown, the benefits of postmastectomy
electron beam therapy on overall survival for
high-risk breast cancer can be extrapolated to
IBC (see Chapter 15). The exact protocol for
postmastectomy electron beam therapy for
IBC can vary among institutions and with
the response to chemotherapy.
Suggested Readings
1. Brito RA, Valero V, Buzdar AU, et al. Long-term
results of combined-modality therapy for locally
advanced breast cancer with ipsilateral supraclavi-
cular metastases: The University of Texas M.D.
Anderson Cancer Center experience. J Clin Oncol
2001;19:628–633.
2. Cancer WG, Carey LA, Calvo BF, et al. Long-term
outcome
of
neoadjuvant
therapy
for
locally
advanced breast carcinoma: effective clinical down-
staging allows breast preservation and predicts
outstanding local control and survival. Ann Surg
2002;236:295–302.
3. Cristofanilli M, Buzdar AU, Hortobagyi GN. Update
on the management of inflammatory breast cancer.
Oncologist 2003;8(2):141–148.
4. Cristofanilli M, Valero V, Buzdar AU, et al. Inflam-
matory breast cancer (IBC) and patterns of recur-
rence: understanding the biology of a unique
disease. Cancer 2007;110(7):1436–1444.
5. Gonzalez-Angulo AM, Hennessy BT, Broglio K, et al.
Trends for inflammatory breast cancer: is survival
improving? Oncologist 2007;12(8):904–912.
6. Lee MC, Newman LA. Management of patients
with locally advanced breast cancer. Surg Clin
North Am 2007;87(2):379–398, ix.
7. Newman LA. Management of patients with locally
advanced breast cancer. Curr Oncol Rep 2004;
6(1):53–61.
8. Singletary SE, McNeese MD, Hortobagyi GN. Feasi-
bility of breast-conservation surgery after induction
chemotherapy for locally advanced breast carci-
noma. Cancer 1992;69:2849–2852.
9. Waljee JF, Newman LA. Neoadjuvant systemic ther-
apy and the surgical management of breast cancer.
Surg Clin North Am 2007;87(2):399–415.
10. Walshe JM, Swain SM. Clinical aspects of inflam-
matory breast cancer. Breast Disease 2005-2006;
22:35–44.
11. Yang CH, Cristofanilli M. Systemic treatments
for inflammatory breast cancer. Breast Disease
2005–2006;22:55–65.
296
SURGICAL FOUNDATIONS: ESSENTIALS OF BREAST SURGERY

20
Surveillance of the Patient
with Breast Cancer after
Treatment
PATTERNS OF RECURRENCE FOR
BREAST CANCER
Local Recurrence
Regional Recurrence
Distant Recurrence
Second Primary Breast
Cancers
Nonbreast Cancers
TREATMENT-RELATED
TOXICITY
SURVEILLANCE FOR PATIENTS
WITH BREAST CANCER
Recommended Follow-up for
In Situ Cancer
Recommended Follow-up for
Invasive Cancer
Not Recommended Follow-up
Studies
Surveillance of the Patient with Breast Cancer after
Treatment: Key Points
Understand the importance of adequate surveillance after breast
cancer treatment.
Know the common patterns of recurrence of breast cancer.
Develop a follow-up schedule for patients with breast cancer based on
stage of presentation.
Understand the risks of second primary cancers after successful treatment
of breast cancer.
Know the limitations of surveillance studies and the risks of ordering
excessive tests in the surveillance period.
Know the treatment-related toxicities that must be monitored for after
treatment.
297

Throughout the their lifetime, women treated
for breast cancer face a risk of disease recur-
rence. Following completion of their treatment,
patients require surveillance to recognize and
treat potentially curable recurrences and iden-
tify second primary breast cancers (Box 20–1).
Understanding the patterns of breast cancer
relapse, and the benefits and down sides of sur-
veillance testing is necessary to establish a cost-
effective follow-up strategy.
Breast cancer can recur many years after
therapy. Traditionally, the annual frequency
of recurrence has been relatively predictable,
highest during the first 3 years and gradually
declining thereafter. Most recurrences occur
within the first 5 years of therapy, and as a
result, the greatest emphasis on surveillance
is during this time period. Although this is still
true, it may be in a state of flux because newer
agents and longer periods of systemic therapy
(such as the use of aromatase inhibitors [AIs]
after 5 years of tamoxifen) may alter these
recurrence patterns. A higher percentage of
patients are returning with recurrent disease
beyond that 5-year window, so lifelong surveil-
lance is necessary.
Who is going to perform this follow-up is still
a matter of debate. After completing therapy,
patients with breast cancer may now have a
team of doctors, including a surgeon, a radia-
tion oncologist, and medical oncologist. It is
important to avoid redundancy, so coordina-
tion of follow-up among all treating physicians
is necessary. The follow-up does not necessarily
need to be with an oncologist. The primary care
provider may also assume the responsibility to
follow the patient after he or she completes
therapy. This is not only more cost effective,
but several studies have demonstrated that
prognosis is no worse with primary care provi-
ders following the patient than with cancer
specialists. However, most of these studies
provided specialized training to the primary
care physician in the follow-up of patients with
breast cancer, and their participation in the
study
indicated their interest in following
patients with cancer. This may not be true for
all primary care physicians.
Patterns of Recurrence
for Breast Cancer
Understanding the patterns of recurrence for an
individual patient’s breast cancer helps focus
the surveillance and allows the physician to
tailor the appropriate follow-up strategy to each
patient. As stated, the majority of breast cancer
recurrences occur within the first 5 years after
therapy, although they can occur later than
this. For this reason, most of the emphasis on
surveillance is within the first 5 years. Patients
with ductal carcinoma in situ (DCIS) have a
low risk of distant recurrence. Therefore, the
major risks these women face are of local
recurrence or a second primary cancer. Women
with large primary tumors or with nodal metas-
tases are at a much higher risk of both loco-
regional and distant metastases (in addition
to second primary cancers). The surveillance
should therefore reflect this.
Local Recurrence
Local recurrence is not only a problem for
women who underwent BCT, but chest wall
recurrences may also occur after a mastectomy.
Local
recurrence
after
breast-conservation
therapy (BCT) typically presents in a similar
fashion to primary breast cancer, including
abnormal
mammograms,
palpable
masses,
or other symptoms such as nipple discharge.
Local
recurrence
following
a
mastectomy
most commonly presents as nodularity in or
under the skin of the chest wall. This is most
often near the mastectomy scar.
The risk of local recurrence will vary depend-
ing on the initial stage of the patient and treat-
ment. The risk of a local recurrence after a
mastectomy correlates with size of the original
tumor, metastases in the regional lymph nodes,
the use of adjuvant therapy, and the use of
chest wall radiation. Additional factors that
have been associated with local recurrence after
BCT include positive margins, grossly multifo-
cal disease, high-grade angiolymphatic inva-
sion,
and
young
age.
Overall,
however,
women who undergo BCT or mastectomy have
relatively
similar
rates
of
local
recurrence,
approximately 10% to 15% over 10 years. They
will differ in their timing. Although most chest
wall recurrences are detected within the first
BOX 20–1 GOALS OF BREAST
CANCER FOLLOW-UP


Detect and treat recurrence of the
cancer


To diagnose and treat second cancers


To address complications of therapy


To gather data for research purposes
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SURGICAL FOUNDATIONS: ESSENTIALS OF BREAST SURGERY

2 to 3 years after surgery, local recurrences are
more commonly detected 3 to 4 years after
breast conservation, sometimes longer.
After BCT, it is sometimes difficult to differ-
entiate between a true local recurrence and a
new ipsilateral primary breast cancer. In either
case, the woman will require a mastectomy
because radiation cannot be used a second
time; however, whether this is a true recur-
rence or a second primary may impact the deci-
sion to use adjuvant therapy. In general, a
second primary tumor occurs later than a local
recurrence, may be in a different quadrant of
the breast, and may have a different histology
than the original tumor. Often a careful review
of the pathology and estrogen receptor (ER),
progesterone
receptor
(PR)
and
Her-2/neu
expression of both the original primary and
the new tumor can help make the diagnosis,
but this is not a guarantee. In some cases, a
previously ER-positive tumor can recur as an
ER-negative tumor. In fact, the opposite can
sometimes occur; a previously ER-negative
tumor may recur as ER positive.
Although women who underwent BCT and
had a local recurrence have a worse prognosis
than women who did not have a local recur-
rence, the majority of these women will be sal-
vaged by mastectomy. The outcome is less
optimistic for women who have a chest wall
recurrence after a mastectomy. This carries a
much worse prognosis because nearly one third
of these women will have distant disease at the
time of their local recurrence. A chest wall recur-
rence should be thought of as a harbinger of dis-
tant disease, and a staging workup (history and
physical, computed tomography [CT] of chest/
abdomen/pelvis and bone scan) should be per-
formed before proceeding with salvage therapy.
Although it is not imperative, it is not unrea-
sonable to perform a staging work-up in a
woman with an in-breast recurrence after BCT.
Regional Recurrence
In addition to local recurrences, recurrences in
the regional basins can occur. These include
the ipsilateral axillary, infraclavicular, supra-
clavicular, and internal mammary nodes. Not
common, regional recurrences occur in only
1% to 3% of cases.
Although
there
was
some
concern that
the use of sentinel lymph node (SLN) biopsy
may increase this, to date that has not been
demonstrated.
Axillary,
infraclavicular,
and
supraclavicular recurrences most commonly
present as a palpable mass in these regions. In
some cases, axillary recurrence may present as
a new-onset lymphedema. Although lymph-
edema may occur many years after treatment,
its onset should prompt the consideration of
regional recurrence, especially if no other expla-
nation for its arrival is noted. In other cases,
axillary
or
supraclavicular
recurrences
may
present as pain in the arm and shoulder or
increasing sensory or motor loss in the arm or
hand. These symptoms are often as a result of
brachial plexus involvement (although they
may be caused by cervical spine metastases).
CT, magnetic resonance imaging (MRI), and
bone scan can help make the diagnosis and
should be considered in any patient with new
onset pain, paralysis, paresthesias, or lymph-
edema, even in the absence of palpable disease.
Internal mammary recurrences often present as
a deep, fixed mass in an intercostal space at the
ipsilateral sternal border. These often first pres-
ent with pain and tenderness, without a notice-
able mass. It may be difficult to differentiate
from a chest wall recurrence or sternal metasta-
sis. Also in the differential of parasternal pain
are costochondritis (Tietze syndrome), neu-
roma, or radiation-induced sarcoma. Persistent
pain should prompt a CT, bone scan, or MRI
to make the diagnosis.
Sometimes it is not completely clear what type
of a recurrence is present. Masses that appear
along the sternal border may have originated
from the skin flap or chest wall (local recurrence),
internal mammary node (regional recurrence), or
a sternal metastasis (distant recurrence). Masses
inferior to the clavicle could be from the skin flap
(local) or infraclavicular nodes (regional). Masses
in the pectoralis muscle may be chest wall (local)
or from Rotter nodes (regional). The presence of
nodal tissue histologically can help make the
diagnosis, but the node may be completely
replaced. Because of the overlap between local
and regional recurrences, they are often reported
together as locoregional recurrence (LRR).
Distant Recurrence
The greatest fear for patients with breast cancer
and their physicians is that of distant recur-
rence because this marks a shift from a curable
disease to a treatable, but ultimately fatal dis-
ease. In the United States, few patients present
with metastasis, approximately 6% to 7%.
Therefore
the
overwhelming
majority
of
women with stage IV disease represent distant
recurrence among treated patients.
The risk of recurrence is directly related to the
size and grade of the primary tumor and the
299
20—SURVEILLANCE OF THE PATIENT WITH BREAST CANCER AFTER TREATMENT

presence
of
disease
in
the
lymph
nodes.
Although we commonly talk about 5-year sur-
vival, and many women consider reaching that
milestone as evidence of cure, over 25% of all
metastases occur past 5 years from diagnosis.
Much of this is a result of improved systemic
therapies and prolonged hormonal therapy,
and thus this percentage may even be higher
in patients who are hormone-receptor positive.
Breast cancer has the potential to return almost
anywhere in the body, but the most common
initial sites are bone, liver, and lung. Although
brain is often mentioned here, fewer than 5%
of patients will manifest central nervous system
metastases as the first site of metastatic disease.
Second Primary Breast Cancers
One of the most significant risks for the devel-
opment of breast cancer is a previous history
of breast cancer. Thus, breast cancer survivors
are at an increased risk of a second primary
cancer, particularly if they have a strong fam-
ily history or known inherited predisposition
to breast cancer. Typically, we estimate the risk
of a second primary breast cancer as 0.8% per
year. This is based on data from Memorial
Sloan Kettering of patients followed for a
median of 18 years. Thus in the first 5 years
after therapy, 4% of women will develop a
second primary cancer. By 20 years, this num-
ber rises to 16%. However, this risk was age
dependent; women under 45 had an average
annual rate of 1%, whereas women older than
50 and an average annual rate of 0.5%. For
women who were initially ER positive and
underwent 5 years of adjuvant hormonal ther-
apy, the risk of a second primary cancer
dropped by approximately 50%. For women
with a breast cancer gene (BRCA) 1 or 2 muta-
tion, the risk of a second primary cancer is
much higher (see Chapter 8). Second primary
breast cancers more commonly occur later,
past the 5 year mark, necessitating long-term
surveillance.
Because of this risk of a second primary can-
cer, many women may have undergone a pro-
phylactic contralateral mastectomy at the time
of their treatment. Although this is an effec-
tive strategy, it does not completely eliminate
the chance of a second primary tumor. Pro-
phylactic mastectomy will reduce the risk of a
new cancer by over 95%, but that still leaves
a small chance of a new primary tumor in
residual breast tissue. Therefore, surveillance
is still mandated in women who have had
bilateral mastectomies.
Nonbreast Cancers
Often lost in the conversation is the fact that
most women with breast cancer will be suc-
cessfully treated for their cancer and will go
on to have an expected survival no different
than had they never been diagnosed. As such,
they need to have continued surveillance for
new primary nonbreast tumors. Many women
and physicians focused on a recurrence of the
first cancer, tending to overlook screening
guidelines for other cancers such as colon can-
cer. It is important to make sure women con-
tinue their recommended screening programs.
In addition, women who have had breast can-
cer may be at higher risk of nonbreast cancers
either because of common risk factors or as a
result of therapy (Box 20–2). Radiation therapy
increases the risk of sarcoma; chemotherapy
can increase the risk of leukemia; and tamoxifen
increases the risk of uterine cancer. Women with
breast cancer have an increased risk of ovarian
cancer, especially those with a known or sus-
pected BRCA 1 or 2 mutations. An increased risk
of melanoma among patients with breast cancer
has been suggested, although this is less clear.
Treatment-Related Toxicity
Finally, it is important to remember that breast
cancer survivors have several treatment-related
toxicities (Table 20–1). Most commonly, this
is related to early menopause as a result of
chemotherapy-induced ovarian failure or ovar-
ian ablation, or treatment with selective estro-
gen receptor modulators (SERM).
Many women with breast cancer will have
the onset or worsening of hot flashes after
therapy. The most effective therapy, estrogen,
is contraindicated in breast cancer survivors.
BOX 20–2 OTHER PRIMARY
CANCERS AT HIGHER RISK AMONG
BREAST CANCER SURVIVORS


Ovarian cancer


Endometrial cancer (after treatment with
tamoxifen)


Myeloid leukemia (after treatment with
high cumulative doses of alkylating
agents or anthracyclines)


Angiosarcoma (after chest wall
irradiation)


Lymphangiosarcoma (in patients with
lymphedema; Stewart-Treves)
300
SURGICAL FOUNDATIONS: ESSENTIALS OF BREAST SURGERY

This is particularly true for patients who are ER
positive and generally true even for patients
who are ER negative. Options for therapy of
hot flashes in breast cancer survivors include
selective serotonin-reuptake inhibitors (SSRIs),
the SSRI and norepinephrine-reuptake inhibi-
tor, venlafaxine, and the anticonvulsant, gaba-
pentin. These may reduce the frequency and
severity of hot flashes by 50%. However, par-
oxetine can interfere with tamoxifen activa-
tion and should not be used in women on
tamoxifen.
Early menopause can increase the risk of
osteopenia, osteoporosis, and fractures among
breast cancer survivors, as can the use of AIs.
In contrast, postmenopausal women on tamox-
ifen have a reduced risk. In addition to standard
recommendations (calcium and vitamin D,
weight-bearing exercise), measurement of bone
mineral density is recommended every 1 or
2 years for all breast cancer survivors, particu-
larly those on AIs (bone density scans should
be performed before the initiation of an AI).
Bisphosphate therapy should be initiated if
osteoporosis is documented and may play a
role in the osteopenic patient on an AI.
Another risk of treatment is cardiovascular
disease. Radiation therapy to the left chest
wall has been associated with an increase
of 20% to 30% in the long-term risk of car-
diac events, although this is decreasing with
newer techniques. Early menopause increases
risk, as does chemotherapy with anthracy-
clines or trastuzumab, whereas tamoxifen
may
decrease
risk.
Regardless,
all
breast
cancer survivors should be advised to eat
right, exercise, avoid tobacco, and control
cholesterol
and
blood
pressure.
Although
no
specific
monitoring
is
recommended,
patients
showing
signs
of
cardiovascular
compromise should be immediately referred
to a cardiologist for evaluation.
Surveillance for Patients with
Breast Cancer
The appropriate surveillance of patients with
cancer is a difficult subject because there are
several competing ideologies. Patients are often
desirous of frequent and intensive surveillance,
using the most advanced technologies. This is
understandable, given the anxiety surrounding
their diagnosis, and the individual patient
would not be expected to focus on issues
related to health care economics. Patients, in
arguing for more intensive follow-up, would
argue that there is an immeasurable psycholog-
ical benefit to receiving the news that they
have no evidence of disease recurrence.
However, there are many negatives to inten-
sive screening, beyond issues related to cost
and
availability.
First and
foremost,
there
are no randomized trials demonstrating a sur-
vival benefit to more intensive surveillance
beyond history, physical, and mammography.
Randomized trials of women with nonmeta-
static
breast
cancer
failed
to
demonstrate
any impact on overall mortality compared to
more intensive surveillance. Much of this is
a result of the fact that the therapies we have
available
to
treat
stage
IV
breast
cancer
have
little
impact
on
extending
survival.
Instead, they primarily delay or diminish the
symptoms associated with metastatic disease.
Initiating
disease
before
the
onset
of
symptoms is therefore of minimal benefit.
Finding the disease earlier only serves to
TABLE 20–1
Possible Side Effects
of Breast Cancer Treatment
Symptom
Treatment
Hot flashes
Citalopram
Fluoxetine
Venlafaxine
Gabapentin
Sexual
dysfunction
Counseling or nonhormonal
moisturizing or lubricating
formulas (Replens,
Astroglide), or intravaginal
estradiol preparations
Cognitive
dysfunction
Full evaluation to rule out other
causes
Depression
Counseling, antidepressants
Weight gain
Counseling, diet, exercise
Fatigue
Full evaluation to rule out other
causes
Musculoskeletal
pain
Rule out fractures or bone mets,
nonsteroidal
antiinflammatory drugs or
acetaminophen
Osteopenia/
osteoporosis
Screening for high risk women
Calcium and vitamin D,
exercise, possibly
bisphosphonate
Cardiovascular
disease
Appropriate medical
management
Deep vein
thrombosis
Anticoagulation as indicated
Lymphedema
Physical therapy, preferably by
a lymphedema specialist
301
20—SURVEILLANCE OF THE PATIENT WITH BREAST CANCER AFTER TREATMENT

lengthen the amount of time the patients
know they have stage IV disease, and this has
a significant negative impact on quality of life.
There is also a negative side to obtaining fol-
low-up chest x-rays, CT scans, or even blood
tests. Although there may be that relief in
hearing that there is no evidence of distant
disease, there is a significant amount of stress
experienced in the weeks preceding the test
and in the time between when the test is per-
formed and the clinician notifies the patient
of the results. More importantly, all of these
tests have significant false-negative rates, lead-
ing to further increased anxiety, and addi-
tional
and often
more invasive
follow-up
tests. Detailed and tactful discussions need to
be held with the patient explaining why fre-
quent and intensive monitoring is not typi-
cally performed Box 20–3).
Many physicians, in an attempt to pacify
patients or increase their own level of comfort
(treating the physician rather than treating
the patient), will still obtain yearly blood tests
(complete blood count [CBC], chemistries,
tumor markers) and chest x-rays and fre-
quently follow-up with all patients with breast
cancer (including those with a low risk of dis-
ease recurrence, such as those patients with
DCIS only). Although this may make them
more popular with their patients, the impact
on health care costs is substantial. The esti-
mated cost for this type of screening, compared
to the recommended history and physical and
yearly mammography can be five times higher.
If all physicians used the recommended mini-
malist approach to surveillance, nearly 1 billion
dollars per year could be saved and put toward
other aspects of breast cancer care. And this
would be accomplished without any compro-
mise of patient outcome. It is therefore impe-
rative
that
we
all
practice
cost-conscious
medicine. With that in mind, the recom-
mended surveillance for patients with breast
cancer is detailed next.
Recommended Follow-up for
In Situ Cancer
Patients with DCIS are generally treated by
lumpectomy with radiation therapy (although
the treatment of low-grade DCIS by lumpec-
tomy alone may be considered) or simple
mastectomy. Tamoxifen may be used after
breast-conserving surgery to further reduce
local recurrence. It may also be considered as
chemoprevention for contralateral cancers in
women treated by mastectomy. This is detailed
in Chapter 20.
For the most part, patients with DCIS are at a
low risk of developing either regional or distant
recurrences. The goal of follow-up in these
patients is therefore to look for a recurrent cancer
in a conserved breast or a new cancer in either
breast. The follow-up for patients with DCIS
is limited to history, physical, and mammogra-
phy. History and physical examination should
be performed every 6 months for the first 5 years
and then yearly (Box 20–4).
For
the
patient
being
treated
by
breast
conservation, an ipsilateral mammogram is
recommended after lumpectomy and before
radiation
when
the
patient’s
DCIS
was
BOX 20–4 NATIONAL
COMPREHENSIVE CANCER
NETWORK RECOMMENDED
FOLLOW-UP AFTER TREATMENT
OF BREAST CANCER


History and physical examination
every 4–6 months for invasive cancer
and every 6 months for DCIS for 5 years,
followed by yearly


Mammogram every 12 months


If patient is on tamoxifen:


Annual pelvic examination


If patient is on an aromatase inhibitor or
has treatment related ovarian failure


Monitoring for bone density loss
BOX 20–3 DRAWBACKS TO OVERLY
AGGRESSIVE FOLLOW-UP
STRATEGIES


Cost to the patient and cost to the
health care system.


Limited options for treatment when
asymptomatic distant recurrences are
detected.


No significant improvement in survival
(lead-time bias).


Regularly scheduled physical
examinations detect relatively few
recurrences.


Serum markers have a low sensitivity for
detecting recurrence.


Imaging studies may be false-positive,
prompting unnecessary worry and
additional studies/procedures.
302
SURGICAL FOUNDATIONS: ESSENTIALS OF BREAST SURGERY

diagnosed by microcalcifications. This postlum-
pectomy mammogram assures that all the
calcifications
were
removed.
Occasionally,
residual calcifications may be present, even if
negative margins were obtained around the
DCIS. These should be excised by wire-localized
excision as they (1) may represent residual dis-
ease and (2) will be suspect for local recurrence
at the first surveillance mammogram. Once
radiation is completed, the next ipsilateral
mammogram should be obtained 6 months
later. This will serve as a new baseline mammo-
gram for that side. Any sooner than that is
suboptimal because of the radiation induced
changes
(edema,
skin
changes,
etc.).
Six
months
after
that,
bilateral
mammograms
should be obtained and be performed annually.
There is no data that more frequent mammo-
grams are of benefit. If treatment was delayed
for any reason, it is important to note when
the
last
contralateral
mammogram
was
obtained, so the interval on the contralateral
side is not too much longer than 1 year.
For patients treated by mastectomy, contralat-
eral mammography is performed yearly. If the
mastectomy was reconstructed by means of a
transverse
rectus
abdominis
myocutaneous
(TRAM) flap, there are some radiologists who
would recommend a TRAMogram-mammogra-
phy of the reconstructed breast as part of
the surveillance imaging. Although this is
not a standard recommendation, many cancer
centers routinely perform TRAMograms in addi-
tion to mammograms of the contralateral breast,
particularly for cases of DCIS that required mas-
tectomy. TRAMograms may potentially find cal-
cifications and recurrences before they are
detectable on physical examination.
Recommended Follow-up for
Invasive Cancer
A history and physical should initially be
performed every 3 to 6 months after the com-
pletion of therapy. Patients with a higher risk
of relapse should be seen every 3 months,
whereas low-risk patients can be seen closer
to every 6 months. These follow-ups should
be coordinated with all of the treating physi-
cians. It does not benefit the patient to be seen
three times in 1 month by the surgeon, the
medical oncologist, and the radiation oncolo-
gist. Follow-up care should be coordinated as
not to duplicate effort. In addition, the patient
should continue to follow-up with their pri-
mary care physician because the oncology
team
will
rarely
focus
on
routine
health
maintenance. For patients at lower risk, follow-
up visits can be alternated between the oncolo-
gist and the primary care physician or in some
cases left completely to the primary doctor.
As the patient gets further out from their
treatment, surveillance visits can be scheduled
further apart. The American Society of Clinical
Oncology
recommends
that
patient
visits
should be every 3 to 6 months for the first 3 years
after therapy, every 6 to 12 months for the next
2 years, and then annually after 5 years.
History
When seeing a patient with breast cancer for a
return visit, the history should start by focus-
ing on signs and symptoms related to local or
regional recurrence. Has the patient been
performing her recommended monthly BSEs?
This is crucial because the majority of local
recurrences are discovered by the patient, not
by the physician. Has the patient noticed any
new masses or changes in the area of the
lumpectomy, or in the case of a mastectomy,
on the chest wall? In the first few months after
surgery and radiation, some posttreatment
changes
are
to
be
expected.
As
swelling
decreases, seromas resolve, and scar tissue soft-
ens, the patient may notice changes in the
region. Has the patient noticed any new
masses in the contralateral breast? In addition
to asking about new lumps in the breasts, the
physician should query about lymphadenopa-
thy either under the arm or in the neck. These
questions will also serve to remind the patient
that they should be performing BSEs of both
breasts and lymph node self-examinations. If
they are not, time should be taken to review
how to perform a self-examination.
The history should then shift toward symp-
toms consistent with metastatic disease. This
should begin with constitutional symptoms;
weight loss or gain, changes in appetite or
energy levels, fatigue, etc. A full review of
symptoms should be performed going by sys-
tems. As breast cancer may metastasize to the
brain, central nervous system symptoms such
as headaches, nausea/vomiting, syncopal epi-
sodes, vision changes, or nerve palsies should
be reviewed. If patients have symptoms, it is
important to ask how long these symptoms
have been present. Quite often the patient will
report headaches, but her headaches predate
the breast cancer by several years.
Breast cancer commonly recurs in the lung
and liver; however, the patient has to have
rather advanced disease to cause symptoms.
303
20—SURVEILLANCE OF THE PATIENT WITH BREAST CANCER AFTER TREATMENT

Nonetheless, the patient should be asked about
cough, shortness of breast, pain with deep inspi-
ration or pleuritic chest pain, or right upper
quadrant pain, melena, or changes in bowel
function or habits. Finally, questions regarding
constant aching pain may elicit the presence of
bone metastases. One of the most challenging
aspects of the surveillance examination is differ-
entiating the mild aches and pains that all
patients will get as they get older from symp-
toms that may suggest recurrent disease.
Many patients who are ER positive being
seen for surveillance will be on hormonal ther-
apy, such as tamoxifen or Arimidex. It is there-
fore important to ask about symptoms related
to the complications of these therapies. The
risk of uterine cancer is significantly increased
with tamoxifen, particularly among women
over the age of 50. Uterine cancers typically
present with abnormal vaginal bleeding. This
needs to be asked of patients, and any abnor-
mality worked up because most uterine can-
cers are highly curable in the early stages.
The use of routine endometrial biopsies is not
necessary. Tamoxifen also increases the risk of
deep venous thrombosis, so patients should
be queried on leg or calf pain, swelling, or
other signs of thrombotic disease. AIs do not
appear to carry the same risk of uterine cancer
or thrombotic disease, but they do have an
increased risk of bone pain and osteoporosis.
Physical Examination
As with the history, the physical examination
should focus on LRR and distant recurrence.
The examination should include a thorough
examination of the treated breast (or chest wall
in the case of a mastectomy) and the opposite
breast. An accurate description of the examina-
tion in the medical records is important to
document postoperative and postradiotherapy
changes. These may even include diagrams of
the treated breast. This helps the examiner fol-
low these changes over time and recognize
new changes. The examination should include
a search for axillary, supraclavicular, and cervi-
cal adenopathy and should note the presence
of lymphedema on the affected side. Not only
may this allow for early intervention, but the
subsequent development of lymphedema may
also represent a regional recurrence.
The remainder of the examination should
focus on distant recurrence. Palpation of the
spine, sternum, and pelvis for bone tenderness
may reveal bony metastases. A heart and lung
examination is crucial, not only because of the
possibility of pulmonary metastases, but also
because several breast cancer therapies may
have negative effects on cardiac performance
(Adriamycin, radiation, Herceptin). Right upper
quadrant tenderness or hepatomegaly may be a
sign of liver metastases, and a neurologic exami-
nation should be performed to rule out central
nervous
system
metastases.
In
women
on
tamoxifen, calf tenderness or a positive Homan
sign may be evidence of a deep venous throm-
bosis. A yearly gynecologic examination is also
important in women on tamoxifen who have
not undergone hysterectomy. Because it would
be unlikely that the breast surgeon would per-
form this examination, it should be verified
with the patient that they are having this done
by their gynecologist or primary care physician.
Mammography
Mammography not only detects local recur-
rences, but also second primary breast cancers,
which
breast
cancer
survivors
are
at
an
increased risk of developing. A new baseline
mammogram of the treated breast should be
obtained at 6 months. Bilateral mammography
should then be obtained yearly after that. More
frequent mammography does not appear to
improve outcome and should only be per-
formed when an abnormality is detected on
physical examination. It is important to note
when the last mammogram was obtained on
the contralateral breast because sometimes the
focus on the treated breast leads to intervals
greater than 1 year between mammograms on
the unaffected side.
Referral for Genetic Counseling
Women at high risk of harboring the BRCA 1
or 2 mutation or women at a higher risk of a
second primary breast cancer should ideally
undergo
genetic
counseling
and
possibly
genetic testing before their treatment because
this might affect their decisions regarding local
therapy and prophylactic surgery (Box 20–5).
However, some women, overwhelmed by their
cancer diagnosis, are not prepared to think
about the implications of genetic testing or
prophylactic surgery. If this had not been
addressed pretreatment, then it should be reas-
sessed in the immediate surveillance period.
Even in women who do not desire prophylac-
tic surgery, genetic counseling and testing
may alter surveillance strategies and may have
implications
regarding
additional
measures
(such as oophorectomy).
304
SURGICAL FOUNDATIONS: ESSENTIALS OF BREAST SURGERY

Not Recommended Follow-up
Studies
It seems logical that intensive follow-up should
lead to an earlier recognition of distant disease
and more successful treatment. However, when
one considers the question more closely, taking
into account the likelihood of finding disease,
the possibility of false-positives, and the impact
of initiating therapy earlier in stage IV disease, it
becomes apparent that this assumption is false.
Thus, in asymptomatic patients, the routine
use of blood tests and radiologic imaging to
detect distant disease is not recommended. The
false-positive rates for these tests can be as high
as 50%. False-positives raise anxiety and usually
lead to additional studies and possibly invasive
biopsies.
Two
randomized
trials
compared
intensive screening to routine clinical evalua-
tion, and neither found any impact on survival.
In fact, one found a significant decrease in qual-
ity of life associated with intensive screening.
This is, however, a field that is constantly
evolving. Although today there is little evi-
dence that finding metastatic disease earlier
does not seem to improve outcome, as sys-
temic therapies and imaging studies improve,
this might change.
Blood Tests
Blood chemistries are often recommended as a
surveillance tool, but their use is limited. Liver
function tests may be elevated in patients with
liver metastases, but they are often falsely ele-
vated in patients without metastases and rarely
lead to the detection of disease much earlier
than the onset of symptoms. Other tests, such
as C-reactive protein (CRP) or erythrocyte sedi-
mentation rate (ESR), the acute phase reactants,
can also be elevated with metastatic disease,
but again are non-specific and not routinely
recommended. CBC has little impact on the
early recognition of distant disease.
Several tumor-associated antigens can be
detected
in
the
serum,
such
as
CA15-3,
CA 27.29 and CEA. CA-15-3 and CA-27-29 are
glycoproteins secreted by breast cancer cells,
whereas CEA belongs to a family of glycopro-
teins with increased expression on a number of
cancers, including breast. Their presence may
be predictive of a breast cancer relapse, but they
do not have a particularly high sensitivity or
specificity. They may fluctuate greatly between
tests, making interpretation difficult. These
markers are much more useful in monitoring
patients with documented advanced disease
and to date are not recommended for routine
surveillance following treatment.
Chest X-Rays
One of the most commonly used tests for sur-
veillance after cancer treatment is the chest
x-ray. Breast cancer can recur not only as lung
metastases but in the pleura (resulting in an
effusion) or the mediastinum. However, chest
x-rays are rarely useful in detecting asymp-
tomatic recurrences and are not necessary
for routine surveillance. Less than 5% of
patients
will
present
with
asymptomatic
intrathoracic recurrences detected on chest
x-ray. Therefore, the number of yearly chest
x-rays needed to find a single recurrence is
staggering, certainly not cost effective and
not recommended.
Computed Tomography Scans
or Positron Emission Tomography
Scans
Both CT scans of the chest, abdomen, and
pelvis and PET scans have been investigated
as follow-up instruments in small, single insti-
tution trials with variable results. There are no
large prospective trials and the routine use of
these tests is not recommended.
Bone Scans
The skeletal system represents the most com-
mon site of distant relapse, so it makes sense
that bone scans may detect a more significant
BOX 20–5 CRITERIA FOR REFERRAL
OF BREAST CANCER PATIENT TO
GENETIC COUNSELING


Age <40


Ashkenazi Jewish heritage


History of bilateral breast cancer


History of ovarian cancer


First- or second-degree relative with
history of ovarian cancer


First-degree relative with history of
breast cancer before age 50


Two or more first- or second-degree
relatives with breast cancer


First- or second-degree relative with a
history of bilateral breast cancer


Male relative with history of breast
cancer
305
20—SURVEILLANCE OF THE PATIENT WITH BREAST CANCER AFTER TREATMENT

number of asymptomatic recurrences. How-
ever, in a prospective study by the National
Surgical and Adjuvant Breast Project (NSABP)
of over 2500 women with stage II breast can-
cer, routine bone scans have minimal benefit,
with only 0.6% detecting an asymptomatic
recurrence. This and other similar studies
failed to provide justification for the routine
use of bone scans.
In addition, the overall strategy of intensive
surveillance using serial bone scans, liver ultra-
sounds, chest x-rays, and blood tests has been
examined in two prospective randomized stud-
ies. Both studies showed that most patients
with metastatic disease will present with symp-
toms rather than on imaging studies and nei-
ther study was able to demonstrate a benefit
to survival or an improvement in quality of life
with intensive screening.
Magnetic Resonance Imaging
of the Breast
The use of more sensitive breast-screening tech-
niques such as MRI has been increasing in both
the screening and surveillance of breast cancer.
MRI has been a double-edged sword, finding
cancers not detected by mammography but also
finding many benign lesions, lowering the
specificity and raising the false-positive rate.
The routine use of MRI in the surveillance of
breast cancer patients is not recommended.
There are, however, some women for whom
MRI might be reasonable. These include women
with a known BRCA 1 or 2 mutation who opted
for breast conservation rather than bilateral mas-
tectomy. Although it may be tempting to use
MRI surveillance in women who had a mammo-
graphically occult breast cancer, there is no data
to suggest that mammography is more likely to
miss a second cancer in these women.
Suggested Readings
1. GIVIO Investigators. Impact of follow-up and testing
on survival and health-related quality of life in
breast cancer patients: a multicenter randomized
controlled trial. JAMA 1994;271:1587–1592.
2. Hayes DF. Follow-up of patients with early breast
cancer. N Engl J Med 2007;356(24):2505–2513.
3. Khatcheressian JL, Wolff AC, Smith TJ, et al. American
Society of Clinical Oncology. American Society of
Clinical Oncology 2006 update of the breast cancer
follow-up and management guidelines in the adjuvant
setting. J Clin Oncol 2006;24(31):5091–5097.
4. Rosselli Del Turco M, Palli D, Cariddi, et al. Intensive
diagnostic follow-up after treatment of primary
breast cancer: a randomized trial. JAMA 1994;271:
1593–1597.
5. Rutgers EJ. Follow-up care in breast cancer. Expert
Rev Anticancer Ther 2004;4(2):212–218.
306
SURGICAL FOUNDATIONS: ESSENTIALS OF BREAST SURGERY

21
Management of Breast
Cancer Recurrence
LOCAL RECURRENCE
Presentation of Local
Recurrences
Diagnostic Workup of Local
Recurrence
Treatment of Local Recurrence
after Breast-Conserving
Therapy
Treatment of Local Recurrence
after Mastectomy
Management of the Axilla after
Local Recurrence
REGIONAL RECURRENCE
Treatment of Axillary Recurrence
Management of Supraclavicular
Recurrence
USE OF SYSTEMIC THERAPY
AFTER LOCOREGIONAL
RECURRENCE
SURGERY IN STAGE IV DISEASE
Patient Selection for Surgery
Resection of Specific Metstatic
Sites
Liver Metastases
Brain Metastases
Bone Metastases
Breast Surgery in the Face of
Stage IV Disease
PRINCIPLES OF SYSTEMIC
THERAPY FOR METASTATIC
BREAST CANCER
Management of Recurrence: Key Points
Know how to look for a local recurrence and diagnostic workup if
a recurrence is detected.
Understand the treatment options for the patient with a local recurrence after
breast-conserving therapy or after mastectomy.
Develop an algorithm for the regional management of the patient with a
local recurrence.
Know the management of the patient with an axillary or supraclavicular
recurrence.
Understand the potential role of surgery for patients with metastatic disease.
Be familiar with the principles of systemic therapy in the patient with stage
IV breast cancer.
307

Following surgery for breast cancer, patients can
recur in a variety of methods (Box 21–1). A local
recurrence may be an in breast recurrence in the
case of women treated by breast-conserving
therapy (BCT) or a recurrence on the chest wall
for patients who underwent a mastectomy.
A regional recurrence is defined as recurrent dis-
ease in the regional lymph nodes, either the
axillary, supraclavicular, infraclavicular, or inter-
nal mammary lymph nodes. Finally, a distant
recurrence refers to the development of meta-
static disease outside of the breast/chest wall
and regional nodes. The approach to recurrent
disease is multidisciplinary. Surgery plays a
major role in the management of locoregional
recurrence. The role of surgery in the manage-
ment of metastatic disease is more limited.
The clinical picture of recurrent breast cancer
is changing as the treatment of primary breast
cancer changes. The increasing use of neoadju-
vant
chemotherapy
to
downsize
primary
tumors and allow for BCT or the use of post-
mastectomy radiation for women at high risk
of chest wall recurrence has certainly contribu-
ted to this changing picture. So has the use of
sentinel lymph node (SLN) biopsies, resulting
in a dramatic increase in the number of women
who have not had previous axillary lymph
node dissection (ALND). Advances in systemic
therapy have led to delays in local recurrence
rates and possibly an increase in local recur-
rence as survival from breast cancer increases.
The management of recurrent disease is
rarely
straightforward,
particularly
because
these changes in management have led to sce-
narios for which there is little data to guide
therapy decisions. As the management of
locoregional disease rarely consists of just one
specialty, it is recommended that many of these
patients
be
presented
at
multidisciplinary
tumor boards before commencing with a treat-
ment plan. With multimodality treatment,
long-term disease control is attainable after a
locoregional recurrence, and patients should
be approached with curative intent. This chap-
ter will review the management of locoregional
recurrence, focusing on the role of surgery. In
addition, the role of the surgeon in the treat-
ment of metastatic disease is reviewed.
Local Recurrence
Several factors may ultimately lead to the
development of a local recurrence (Box 21–2).
The incidence of local recurrence will depend
on the stage of the primary cancer and the
treatment the woman received. The use of
lumpectomy alone, rarely recommended, is
associated with a high rate of local recurrence.
Women who undergo BCT or mastectomy
have relatively similar rates of local recurrence,
approximately 10% to 15% over 10 years.
There are several differences, however, in the
presentation
of
local
recurrences
between
women who underwent BCT and those who
underwent a mastectomy (Table 21–1).
For most women who undergo mastectomy,
the presence of recurrent disease is almost
always a recurrence of the primary tumor. This,
however, depends on the degree of breast tissue
that the surgeon left behind at the time of the
initial mastectomy. Leaving thick flaps that
include significant breast tissue or not taking
care to excise the axillary tail of Spence (see
Chapter 12) will result in residual breast tissue
that can develop second primary tumors. This
BOX 21–1 DEFINITIONS OF
LOCOREGIONAL RECURRENCE
Recurrence: Reappearance of a treated
cancer in a patient previously considered NED.
Local recurrence: Recurrence in the remaining
breast after breast conservation or in the soft
tissues of the anterior chest after mastectomy.
In-breast tumor recurrence (IBTR): Local
recurrence in the breast after breast-conserving
therapy although it is not always possible to
differentiate IBTR from a second primary tumor.
Regional recurrence: Recurrence in the
ipsilateral axillary, internal mammary, or
supraclavicular lymph nodes.
Distant recurrence: Recurrence anywhere
outside the ipsilateral breast, chest wall, or
regional lymph node basins.
BOX 21–2 POTENTIAL
EXPLANATIONS FOR LOCAL
RECURRENCE


Incomplete excision of the primary
tumor


Unrecognized multifocal or multicentric
disease


Implantation of tumor cells at the time of
surgery


Entrapment of cells within obstructed
lymphatics


Local implantation of systemically
circulating cancer cells
308
SURGICAL FOUNDATIONS: ESSENTIALS OF BREAST SURGERY

is particularly true in women with a breast can-
cer gene (BRCA) 1 or 2 mutation. In contrast, a
second tumor in a breast previously treated for
breast cancer may represent either an in-breast
tumor recurrence (IBTR) or a second primary
tumor. In general, a second primary tumor
occurs later than an IBTR, may be in a different
quadrant of the breast, and may have a differ-
ent histology than the original tumor. In some
cases it is difficult if not impossible to differen-
tiate between the two.
Local recurrences after mastectomy are diag-
nosed earlier than IBTRs. The median time to
recurrence after a mastectomy is 2 to 3 years,
compared with 3 to 4 years after BCT. Local
recurrences can occur much later than this,
however, depending on the use of systemic
therapies.
The implications of a local recurrence on
prognosis also differ between BCT and mastec-
tomy. Both signal an increased risk of addi-
tional disease, but women who have a local
recurrence after BCT tend to have a lower rate
of simultaneous regional or distant metastases
and an improved cancer-specific survival com-
pared to women with a chest wall recurrence.
Both forms of recurrence should prompt a
thorough search for distant disease, and in
the absence of documented metastases, should
be approached with a curative intent.
Presentation of Local Recurrences
A local recurrence in an intact breast is usually
detected by a change in the physical examina-
tion or on surveillance mammography. Physical
examination findings may include a palpable
mass or increased thickening or retraction at
the site of the lumpectomy site. Mammographic
findings may include a new mass, architectural
changes, or the new appearance of calcifica-
tions. However, these changes may not always
represent a local recurrence. Both surgery and
radiation therapy can lead to changes over time
that can be confused with recurrent disease.
Likewise, not all IBTRs detected on physical
examination will be associated with mammo-
graphic change, so a normal mammogram does
not rule out a local recurrence.
Postmastectomy recurrences will differ in pre-
sentation depending on whether or not women
have had breast reconstruction. In patients who
have not had reconstruction, postmastectomy
recurrences are almost always detected on self-
examination or by the physician. These typi-
cally present as nodules in the overlying skin
of the chest wall or subcutaneous nodules.
These may be single or multiple and are often
located near the mastectomy scar, although
recurrences can occur anywhere in the skin
flaps. Suture granulomas, scar, fat necrosis, and
even benign breast disease occurring within
residual breast tissue are also in the differential
diagnosis (Box 21–3). For patients several years
past radiation therapy, a radiation-induced sar-
coma must also be considered.
If a patient has had reconstruction with an
expander/implant, a chest wall recurrence is not
typically hidden by the reconstructed breast
TABLE 21–1
Local Recurrence after Breast-Conserving Therapy versus
Mastectomy
In-Breast Tumor Recurrence After
Breast-Conserving Therapy
Chest Wall Recurrence After
Mastectomy
True recurrence?
Sometimes a second primary
Rarely a second primary
Median time to
recurrence
3 to 4 years
2 to 3 years
Detection
Physical examination or
mammography
Almost always physical examination
Surgical approach
Mastectomy
Resection when feasible and radiation
Implications on prognosis
More favorable
Strong association with systemic disease
BOX 21–3 DIFFERENTIAL
DIAGNOSIS OF A LOCAL CHEST
WALL RECURRENCE


Postradiation or postoperative
change


Foreign body cyst around suture material


Cellulitis


Fat necrosis


A bony nodule on a rib or costal cartilage
from surgical trauma


Sarcoma (radiation-induced). These
typically appear later, at a median of
10 years posttreatment.
309
21—MANAGEMENT OF BREAST CANCER RECURRENCE

because implants are usually placed submuscular.
For patients who have hadtransverse rectus abdo-
minis myocutaneous (TRAM) reconstruction,
recurrences typically occur in the native skin/sub-
cutaneous tissues at the junction between the
TRAM tissues and native tissues. Recurrence in
the TRAM is extremely rare; masses within the
flap are more commonly fat necrosis, although
these can mimic recurrent cancer. For patients
who have had reconstruction after a mastectomy,
mammography is sometimes used for surveil-
lance. Typically this is done in patients who
have had a TRAM flap as opposed to implants.
Occasionally a TRAMogram-mammography will
detect a local recurrence not identifiable on
physical examination.
A rare form of local recurrence is an inflam-
matory recurrence. After breast conservation,
an inflammatory recurrence may present as
diffuse swelling and erythema of the intact
breast, with the associated skin changes asso-
ciated with inflammatory breast cancer (IBC)
such as peau d’orange. These can be difficult
to differentiate from true breast infections,
significant breast lymphedema, or changes
related to radiation therapy. Although rare,
an inflammatory recurrence must be kept in
mind and biopsies performed in any patient
not responding to standard therapy. Inflam-
matory changes can also occur on the chest
wall after a mastectomy. Diffuse infiltration
of the skin and subcutaneous tissues of the
chest wall, resulting in woody induration,
ulceration, and nodules, is a distinct form of
chest wall recurrence known as “carcinoma en
cuirasse.” Unfortunately, the tumor has often
spread beyond standard surgical or radiation
boundaries.
Diagnostic Workup of Local
Recurrence
The first step in the workup of a patient sus-
pected of a local recurrence is a biopsy. For pal-
pable lesions, fine-needle aspiration biopsy
(FNAB) is a quick, simple, and accurate way
of differentiating
between scar tissue and
recurrent disease. However, false-positive and
false-negative results are possible, so the results
must be interpreted in light of the clinical sus-
picion. A negative or inconclusive FNAB of a
clinically suspicious lesion mandates a more
definitive biopsy. Core-needle or excisional
biopsy will provide more definitive results
and will provide tissue to assay for estrogen
receptor/progesterone
receptor
(ER/PR)
and
human
epidermal
growth
factor
receptor
2 (HER-2/neu) expressions. These will not only
help differentiate between a local recurrence
and a second primary tumor, but will also help
guide treatment decisions (Table 21-2).
Once the diagnosis of recurrent disease has
been established, a complete staging workup is
indicated to rule out distant metastases. This is
particularly true for a chest wall recurrence after
mastectomy, which is often referred to as a “har-
binger of distant disease.” It is estimated that
approximately one third of women who have a
chest wall recurrence have distant disease, one
third will develop distant disease, and one third
have an isolated local recurrence. Although the
likelihood of discovering simultaneous distant
disease in women with an IBTR is less, a meta-
static workup is still indicated. One exception to
this would be the woman with an in situ recur-
rence after BCT.
The staging examination typically includes a
thorough history and physical, a computed
tomography (CT) scan of the chest, abdomen,
and pelvis and a radionuclide bone scan. CTscan
or magnetic resonance imaging (MRI) of the
head is not necessary in the absence of neuro-
logic symptoms. Positron emission tomography
(PET) scans have been increasingly used to
restage patients with recurrent disease. PET scans
have a higher sensitivity than CT scans and will
occasionally detect metastases that would have
been missed by CT. However, they have a
decreased specificity and a false-positive rate of
10% or higher. A positive finding on a PET scan
should prompt dedicated imaging of the region
and tissue biopsy to confirm metastatic disease.
Treatment of Local Recurrence
after Breast-Conserving Therapy
The standard approach to an IBTR, assuming
the metastatic workup shows no evidence of
distant disease, is mastectomy, with or without
immediate reconstruction. Lumpectomy alone
is inadequate, associated with a high risk of a
second recurrence, and re-irradiaion is not
recommended. Mastectomy can be performed
with simultaneous reconstruction, although
for patients with a high risk of a second local
recurrence, such as those with significant skin
involvement, it may be preferable to delay
reconstruction. Between 80% and 90% of
patients with an IBTR are amenable to a mas-
tectomy. The remaining 10% to 20% recur
with either advanced or inflammatory disease
and should be treated with systemic therapy
first. Many of these patients may respond to
systemic therapy allowing for mastectomy.
310
SURGICAL FOUNDATIONS: ESSENTIALS OF BREAST SURGERY

Unfortunately, some patients will be diag-
nosed with simultaneous distant metastases.
In this situation, the curative potential of a
simple mastectomy is limited. However, con-
sideration should be given to a palliative mas-
tectomy
to
control
the
locally
recurrent
disease. The decision to perform a mastectomy
in the face of distant disease should take into
consideration the volume of distant disease
and projected survival, the ER/PR expression
of the tumor, chemotherapy history and pre-
dicted response to systemic therapy, and the
nature of the recurrence in the breast and asso-
ciated symptoms.
The survival for patients with an IBTR who
undergo mastectomy is worse than patients
who were treated by BCT and did not experi-
ence a recurrence. The risk of distant disease
ranges from 20% to 40% at 5 years. There are
some factors associated with a significantly
worse outcome after mastectomy for an IBTR
(Box 21–4).
For the rare patient who was treated by
lumpectomy alone, an IBTR can be treated by
either mastectomy or lumpectomy followed
by radiation. The volume of tissue that needs
to be resected and the volume of tissue initially
removed need to be taken into account because
a second attempt at lumpectomy may result in
an unfavorable cosmetic outcome.
Many patients who experience an IBTR after
a lumpectomy and radiation are not willing to
undergo mastectomy and are desirous of a sec-
ond lumpectomy. Several series of women
undergoing second attempts at breast conser-
vation have been reported. These include
patients undergoing lumpectomy alone and
excision with reirradiation of the breast. Several
of these series demonstrate a high rate of sec-
ond local recurrences in the breast, and in some
series, this is associated with a worse outcome.
In addition, the cosmetic outcome may be infe-
rior to that obtained with a mastectomy and
reconstruction. In addition, the complication
rate of reirradiating a breast is extremely high.
Some investigators are examining the use of
partial breast irradiation (PBI) as a method of
reirradiating women after a lumpectomy for
an IBTR, by means of either catheter-based or
intracavitary brachytherapy or limited external
beam irradiation. Although this may be feasi-
ble, this approach should still be considered
investigational only.
Treatment of Local Recurrence
after Mastectomy
In the patient with a chest wall recurrence and
no evidence of distant disease, a multidisciplin-
ary approach is needed for successful manage-
ment. In this situation, combined modality
treatment has the potential to provide long-term
disease control. Even in the presence of distant
metastases, optimal local treatment can signifi-
cantly reduce the morbidity of uncontrolled
local spread. The approach to therapy will
depend on several factors (Box 21–5).
BOX 21–4 FACTORS ASSOCIATED
WITH POOR OUTCOME AFTER
IN-BREAST TUMOR RECURRENCE


Inflammatory type of recurrence


Stage of the primary tumor


Interval between primary treatment and
recurrence (disease-free interval)


An invasive as compared to noninvasive
tumor recurrence


Large or advanced recurrent tumor, skin,
or muscle involvement.


Multicentric tumor recurrence


Lack of hormone receptor expression
TABLE 21–2
Local Recurrence versus Second Primary Tumor
True in-Breast
Tumor Recurrence
Second Primary Tumor
Time to
occurrence
Shorter
Longer
Histology
Similar to primary
Difference in histology, estrogen receptor/progesterone receptor
(ER/PR) expression, human epidermal growth factor receptor
2 (Her-2) overexpression, flow cytometry
Location
Same region as primary
tumor
Outside of boost volume
Implications
on prognosis
Worse
Better
311
21—MANAGEMENT OF BREAST CANCER RECURRENCE

The first decision to be made is whether the
disease is surgically resectable. If it is, then the
wide excision of all gross disease should be
the first step. In some cases this will be a rather
simple excision of the skin nodules with an
adequate margin of normal skin. In other cases,
skin grafting or a tissue flap may be necessary
to fill in the defect. In rare cases, resection to
negative margins may necessitate the resection
of muscle or chest wall. Surgical intervention,
however, should be planned with the intent
of removing all gross disease. Leaving behind
gross disease is associated with a high rate of
subsequent chest wall failures as compared
with patients who undergo complete excision.
The potential for radiation therapy to maxi-
mize disease control is considerably improved
by the excision of all gross disease. In cases in
which this can only be accomplished by more
extensive surgery needed to control disease,
the benefits of surgery (potential for cure or pal-
liation) must be weighed against the risks.
Additional factors such as whether or not the
patient is a candidate for radiation therapy or
systemic therapy should be considered, and
these patients are best evaluated within a multi-
disciplinary setting.
For patients who have had reconstruction,
removal of an implantor TRAM flap is not always
necessary. If complete surgical removal of the
recurrence is possible, it should be undertaken.
In patients who did not receive postmastectomy
radiation, radiation to the reconstructed breast is
also possible. However, it is important to note
that in the case of an implant, capsular contrac-
ture is frequent, and in the case of a TRAM flap,
contraction and shrinkage is possible.
For the patients who were initially treated by
mastectomy alone, external beam radiation ther-
apy is recommended after resection of the
recurrent disease. The field to treat depends on
the patient’s previous treatment and extent of
disease. Optimal management typically involves
treatment to the entire chest wall and draining
lymph node basins. This is true even if the local
recurrence is isolated to a small area because
the risk of subsequent failure in this area is high
if radiation is limited to the chest wall. For the
patient who has not undergone a previous
ALND, treatment should include the chest wall,
axillary, supraclavicular, and internal mammary
lymph nodes. However, this may be altered by
how the axilla is managed surgically.
A more difficult situation is the woman who
underwent postmastectomy radiation and pre-
sents with a chest wall recurrence. Further radia-
tion
is
generally
frowned
on
given
the
significant risks of tissue damage and the low
likelihood that it will control the disease. In
selected cases, retreatment with limited doses of
radiation can be used for palliative purposes,
but this is unlikely to contribute to long-term
cure. The need for radiation will also be influ-
enced by whether systemic therapy is feasible.
These cases should almost always be discussed,
and treatment planned, in a multidisciplinary
setting.
There are other options for women who have
had a chest wall recurrence after mastectomy
with radiation. Hyperthermia (in the tempera-
ture range from 104 F to 113 F [40 C to 45
C]) has been shown to be cytotoxic. Initially,
it was thought that the combination of radia-
tion and hyperthermia would decrease local
recurrence rates because the therapies are com-
plementary,
working
through
different
mechanisms. Unfortunately, randomized trials
failed to demonstrate any added benefit to
hyperthermia,
although
these
trials
varied
greatly in terms of both treatment plans and
patient
eligibility.
For
patients
who
have
already had postmastectomy radiation, com-
bined hyperthermia and radiation (with a
decreased dose of radiation) remains an option,
although reported local control rates vary.
Another approach being examined is photo-
dynamic therapy (PDT). This uses a photosensi-
tizing agent that is taken up by both normal and
malignant tissue but is rapidly cleared from
nonmalignant
cells.
Once
accumulated
in
malignant tissue, the tumors are exposed to a
laser light (the wavelength depends on the
agent used), which induces a phototoxic reac-
tion. This leads to selective necrosis of the
tumor. PDT has been successfully used to treat
cancers of the skin, bronchi, and esophagus
but its use is limited by the depth to which the
BOX 21–5 FACTORS TO CONSIDER
WHEN PLANNING THERAPY FOR
CHEST WALL RECURRENCE


Extent of local disease (single
versus multiple nodules)


Resectability (need for skin grafts, tissue
flaps, or chest wall resection)


Comorbid conditions of the patient


Disease-free interval


History of postmastectomy radiation


History of systemic therapy


Present estrogen receptor/progesterone
receptor status
312
SURGICAL FOUNDATIONS: ESSENTIALS OF BREAST SURGERY

light penetrates. Several small series of PDT for
chest wall recurrences have been reported with
minimal toxicity, although the optimal agents
and doses (of both agent and light) are still
being worked out.
Management of the Axilla after
Local Recurrence
As with primary breast cancer, a local recurrence
may be associated with disease in the regional
lymph nodes. This could either represent
spread from the recurrent tumor or residual dis-
ease not diagnosed at the time of primary treat-
ment. The approach to restaging the axilla has
changed considerably over the past decade with
the advent of SLN biopsy. Before SLN biopsy,
almost all women who experienced an IBTR
had already undergone an ALND. Today, how-
ever, many women with recurrences will have
never undergone an ALND, having had a nega-
tive SLN biopsy at the time of their initial
lumpectomy.
When faced with a local recurrence requiring
surgical therapy, the surgeon must decide how
to
approach
the
regional
lymph
nodes
(Fig. 21–1). This approach will depend on how
the patient was initially treated and what adju-
vant treatments are planned after surgery; thus
the need for repeat axillary staging in the face
of a local recurrence requires a multidisciplin-
ary approach. Factors to consider include the
previous axillary surgery (none versus SLN
biopsy versus ALND), the initial stage of disease
and likelihood of distant metastases, and the
impact of identifying regional disease on adju-
vant therapy decisions. It should go without
saying that any patient with a local recurrence
should have a thorough physical examination
and possibly an ultrasound of the axilla, with
FNAB of any clinically suspicious lymph nodes.
For the patient with an IBTR who has already
undergone a complete ALND and has no clinical
evidence of regional disease, simple mastectomy
alone is sufficient. SLN biopsy may be attempted
in this situation, and although there may be
drainage to a residual axillary node, there is a
high likelihood of aberrant drainage patterns,
with the lymphoscintigraphy showing uptake
in the supraclavicular, internal mammary nodes
(IMN), or contralateral axillary nodes (Fig. 21–2).
The surgeon must decide what the benefit to the
patient would be in going after these sentinel
nodes, either on preventing further recurrence
or adjuvant therapy decisions.
For the woman with an invasive recurrence
after BCT for ductal carcinoma in situ (DCIS),
SLN biopsy is recommended at the time of mas-
tectomy. For the woman with an IBTR who did
not undergo ALND, such as the woman with a
Local Recurrence
Full H&P and
metastatic workup
No clinical evidence of
distant or regional
disease
IBTR after BCT
Chest wall
recurrence after
mastectomy
Previous
ALND
No axillary surgery
or negative SLN only
Simple mastectomy
alone
May attempt SLNB
Mastectomy with SLNB
MRM if SLNB
unsuccessful or +
Resection of chest wall
recurrence only
Previous
MRM
No axillary surgery
or negative SLN only
Presentation at
multidisciplinary
tumor board
Chest wall resection
with or without ALND
• Is RT an option?
• Will nodal status impact adjuvant tx decision?
• Likelihood of regional and distant disease?
Figure 21–1. Management of lymph nodes in the face of a local recurrence.
313
21—MANAGEMENT OF BREAST CANCER RECURRENCE

negative SLN, repeat axillary staging with lym-
phatic mapping and SLN biopsy is still a reason-
able option. Several studies have demonstrated
the feasibility of SLN biopsy in patients who
have had prior breast surgery including BCT.
This includes women who have undergone
prior axillary surgery, including a previous SLN
biopsy. The surgeon should plan ahead of time
what will occur if the lymphatic mapping is
unsuccessful. Although less common than with
a previous ALND, patients with previous SLN
biopsy may have aberrant axillary drainage.
Again, when planning on remapping a patient
with a local recurrence, the surgeon must be
prepared to chase the SLN to more unusual loca-
tions, with the decision how to proceed based
on how the information will affect further
treatment.
For the patient who presents with a chest
wall recurrence after a modified radical mastec-
tomy (MRM), with no clinical evidence of
regional recurrence, he or she does not require
any specific addressing of the axilla. However,
patients who have the axillary nodes intact
(either no SLN was performed, or the SLN was
negative) are a more difficult situation. With
no intact breast, SLN biopsy is not feasible.
Therefore, these patients face two choices. The
first is to only address the chest wall recurrence,
ignoring the axilla. The second is to perform an
ALND at the time of the resection of the chest
wall recurrence. The surgeon must balance the
potential in leaving behind resectable nodal
disease against the fact that many patients
may harbor distant disease and that radiation
or systemic therapy may handle microscopic
regional disease. Again, this decision must be
made in a multidisciplinary setting, taking into
account how treatment might change if an
ALND is performed. If the patient will be receiv-
ing chest wall radiation therapy, the axillary
basin will likely be included, so ALND might
not be needed (and the combination of radia-
tion therapy and ALND carries a high risk of
lymphedema). For patients who have had post-
mastectomy radiation but have an intact axilla
(a relatively small population as positive nodes
are the most common reason for postmastec-
tomy radiation therapy), an ALND should be
performed. Whether the finding of regional dis-
ease would impact the medical oncologist’s
decision to offer systemic therapy should also
be taken into consideration.
Regional Recurrence
In addition to local recurrences, patients may
present with regional recurrences, either isolated
or in conjunction with an in-breast or chest wall
recurrence. Regional nodal recurrences are rela-
tively rare, occurring in only 1% to 3% of cases.
There was some concern that this may increase
with the use of SLN; however, early reports sug-
gest a similarly low regional recurrence rate for
patientswith a negative SLN who do not undergo
ALND. Most regional recurrences are detected on
routine physical examination, although occa-
sionally they are detected on surveillance imag-
ing.
The
presence
of
a
palpable
mass
in
the axilla or supraclavicular fossa should be
considered recurrence until proven otherwise.
In some cases, patients may present new onset
lymphedema, pain in the arm and shoulder, or
increasing sensory or motor loss in the arm or
hand. These latter symptoms are often the result
of brachial plexusinvolvement.These symptoms
may also be caused by cervical spine metastases.
CT, MRI, and bone scan can help make the diag-
nosis and should be considered in any patient
with new onset pain, paralysis, paresthesias, or
lymphedema, even in the absence of palpable
disease.
Internal mammary recurrences often present
as a deep, fixed mass in an intercostal space at
the ipsilateral sternal border. These often first
present with pain and tenderness, without a
noticeable mass. It may be difficult to differenti-
ate from a chest wall recurrence or sternal metas-
tasis. Also in the differential of parasternal pain
are costochondritis (Tietze syndrome), neuroma,
or radiation-induced sarcoma. Persistent pain
INJ
Figure 21–2. Lymphoscintigraphy showing uptake
in the contralateral axilla in a patient who had previ-
ous ipsilateral axillary surgery.
314
SURGICAL FOUNDATIONS: ESSENTIALS OF BREAST SURGERY

should prompt a CT, bone scan, or MRI to make
the diagnosis.
The first step in the approach to regional
recurrence, as with local recurrence, is to rule
out distant disease. In addition to a complete
history and physical, patients should have a
CT of the chest/abdomen/pelvis and a bone
scan. Again, PET scans have also been used in
this situation or when the results of the CT or
bone scan are equivocal.
If there is no evidence of distant disease, the
patient should still be approached with curative
intent, although the likelihood of cure changes
with the location of the regional disease. Isolated
axillary recurrences are most amenable to treat-
ment and are associated with the best long-term
survival. Patients with disease in other nodal
regions are highly likely to develop distant
metastases, and they have a poor outcome.
Treatment of Axillary Recurrence
As with local recurrence, the management para-
digms for regional recurrence are in a state of
flux given the changes in locoregional manage-
ment (SLN biopsy, postmastectomy radiation).
If there is no evidence of distant disease and
the recurrence is surgically resectable, then this
should be the initial approach. For patients
who had a previous SLN biopsy but the axillary
nodes are intact, resection involves a complete
ALND. For patients who had a previous ALND,
resection is still recommended, although this
may be more technically challenging. The sur-
geon should make every attempt to resect the
entire area of recurrent disease. In a previously
operated on axilla, this may be difficult and
require resection of muscle or sacrifice of axillary
structures such as the thoracodorsal or long
thoracic nerve. MRI may be helpful in planning
surgery and determining the necessary extent. If
the axillary recurrence seems difficult to resect,
or unresectable (chest wall involvement, bra-
chial plexus involvement), preoperative therapy
should be considered to improve the likelihood
of complete resection. Intraoperatively, the sur-
geon must assess the adequacy of the original
ALND. In many cases of an axillary recurrence
after ALND, it becomes apparent that only a
superficial clearance or level I only dissection
was performed. In this case, a formal level
I and II dissection should be performed.
If patients are unresectable, even after sys-
temic therapy, radiation is used, although the
ability of radiation to control gross regional
disease is limited, and this is primarily pallia-
tive. If the disease is resected, the question
remains as to whether postoperative radiation
therapy should be used. Factors to be weighed
include the previous use of radiation therapy
(it is important to know the exact fields used
if the patient had previous BCT), the nature
of the recurrence, and the surgery performed.
It is important to remember that the combina-
tion of surgery and radiation to the axilla car-
ries high risks of brachial plexus injury and
chronic lymphedema, but so does uncon-
trolled disease within the axilla.
If the patient had an ALND for a regional
recurrence after a negative SLN, then surgery
alone may be satisfactory if the recurrence is lim-
ited and the resection complete. For patients at
a high risk of a second regional recurrence
(multiple involved nodes, extracapsular exten-
sion), and no history of radiation to the axillary
basin, radiation therapy should be strongly con-
sidered. Radiation should also be used after resec-
tion in patients with no history of axillary
radiation and a regional recurrence after an
ALND. A more difficult situation is the patient
who has had axillary radiation. Limited field reir-
radiation may be considered if the disease can
not be completely resected.
Management of Supraclavicular
Recurrence
Patients with an isolated supraclavicular recur-
rence have worse outcomes than patients with
axillary recurrences, with a high rate of distant
disease. There has been extensive discussion
as to whether or not this should be considered
a regional recurrence or systemic disease, with
little published data to help guide treatment
decisions. Multimodality therapy is the rule,
and with an aggressive approach, a small frac-
tion of patients with an isolated supraclavicular
recurrence may be cured. The sequence of ther-
apy has not been established. Systemic therapy
is typically performed first. The patient should
then be restaged. If there is still no evidence of
distant disease, surgery and radiation therapy
should be considered. Again, the decision
needs to be based on whether the field has been
previously radiated, the feasibility of resection,
and the likelihood of a second supraclavicular
recurrence after surgery (Fig. 21–3).
Use of Systemic Therapy after
Locoregional Recurrence
The use of systemic therapy in patients who
have had a locoregional recurrence but have
315
21—MANAGEMENT OF BREAST CANCER RECURRENCE

no evidence of distant disease remains an unan-
swered question. Because there is a high risk of
distant recurrence among any patient who suf-
fers an in-breast, chest wall or regional recur-
rence, it is usually recommended, especially
considering the large and expanding list of
agents. However, there is little data document-
ing the benefit, if any, on survival. A Cochrane
review of systemic therapy in women with a
locoregional recurrence of breast cancer con-
cluded that there was insufficient evidence to
support this practice. For this reason, rando-
mized trials are ongoing. The International
Breast Cancer Study Group (IBCSG) is conduct-
ing a trial in which patients undergoing surgery
for locally or locoregionally recurrent breast can-
cer are randomly assigned to chemotherapy
(with the regimen chosen at the discretion of
the investigator) or no chemotherapy. Patients
with hormone-receptor-positive tumors also
receive hormone therapy, and the use of trastu-
zumab (Herceptin) is optional for women with
Her2-positive tumors. Patients with resected dis-
ease should be strongly encouraged to partici-
pate in this trial.
Whether the recurrent disease is to be initially
resected or not, it is imperative for the surgeon
to obtain enough tissue to perform ER, PR, and
Her-2-neu staining on. This information will
help guide systemic therapy decisions. It is not
sufficient to rely upon the ER/PR/Her-2 neu sta-
tus of the primary tumor because the recurrence
may be quite different. Even when the tumor
was originally ER/PR negative, the recurrence
may be ER/PR positive (although this is not
common). If the diagnosis of recurrence was
made by FNAB, and systemic therapy before
resection is a consideration, a core biopsy or
excisional biopsy should be performed. If the
disease is resectable, then immunohistochemis-
try (IHC) staining can be performed on the
specimen.
For women who are not participating in the
randomized trial, systemic therapy should be
considered. For women who are ER/PR posi-
tive, hormonal therapy is typically recom-
mended. An aromatase inhibitor (AI) is often
used in postmenopausal women, particularly
if
they
have
already
had
treatment
with
tamoxifen, but also if she has not had any
adjuvant hormonal therapy. A selective estro-
gen receptor modulator (SERM) should be used
in women who recurred within 1 year of treat-
ment with an AI or in premenopausal women.
An alternative approach for premenopausal
women is ovarian suppression/ablation.
Supraclavicular recurrence
No clinical evidence of
distant disease
Full H and P and
metastic workup
Systemic therapy
re-staging
Complete
response in
supraclavicular
node
No previous
radiation
Previous RT
RT alone
Surgery versus
observation
Previous RT
Residual
supraclavicular
disease
No previous
radiation
Surgery alone
Surgery plus RT
for incomplete
resection or high
risk of recurrence
RT alone if not a
surgical candidate
Surgery
No clinical evidence of
distant disease
Figure 21–3. Approach to the patient with a supraclavicular recurrence.
316
SURGICAL FOUNDATIONS: ESSENTIALS OF BREAST SURGERY

Whether chemotherapy should be added to
hormonal therapy in women who are ER/PR
positive is unclear, and a thorough discussion
of the known and unknown risks and benefits
must be discussed with the patient. A stronger
argument for chemotherapy can be made in
the patient whose recurrence is not hormone
responsive.
The success of trastuzumab in conjunction
with doxorubicin and taxane-based chemo-
therapy in the adjuvant setting for patients
expressing Her-2 neu strongly suggests that
women with locoregional recurrences who
are Her-2/neu positive and did not previously
receive trastuzumab, should be treated.
As previously discussed, in some cases of an
isolated regional recurrence, induction systemic
therapy should be considered. These include
cases in which resection would be difficult or in
which the likelihood of distant recurrence is
extremely high. Examples include the large chest
wall or axillary recurrence where adjacent struc-
tures may need to be resected to obtain negative
margins or the isolated supraclavicular recur-
rence. The need to present these patients in a
multidisciplinary setting before proceeding with
surgical therapy can not be overemphasized.
Surgery in Stage IV Disease
Unfortunately, many patients will recur not with
local or regional disease, but with metastatic
disease. When patients present with metasta-
tic disease, the goals of therapy shift from cure
to palliation. Patients with metastatic breast can-
cer are unlikely to be cured. Goals of therapy
shift to symptom control, improved quality of
life, and prolongation of survival. This approach
centers almost exclusively on systemic therapy,
with surgery and radiation reserved for rare situa-
tions in which they can provide palliation (such
as surgery for an enlarging or ulcerating mass or
radiation for bone metastases).
There is, however, some evidence that surgical
resection of metastatic disease may play a role in
the treatment of breast cancer. A subset of stage
IV patients has limited systemic tumor burden
or biologically indolent disease. Although com-
plete remissions are rare, approximately 5% to
10% of patients with stage IV disease will survive
over 5 years, and 2% to 5% may be cured of their
disease. These patients tend to be younger and
healthier with limited metastatic disease. In this
situation, there may be a benefit to multimodal-
ity therapy, including surgery, not only to pre-
vent complications (which may postpone the
need for more toxic systemic therapy) but also
to improve progression-free survival.
Although there are multiple articles suggest-
ing that surgery of stage IV disease may pro-
long survival, it is imperative to remember
that these are exclusively retrospective reviews
and observational studies, which all suffer
from tremendous selection bias. There are no
randomized trials showing resection of meta-
static disease improves survival, and it is
unlikely there ever will be as the number of eli-
gible patients would be small, and few patients
agree to be randomized between surgery and
no surgery. Care must be taken when inter-
preting this data and applying it to individual
patients.
Patient Selection for Surgery
When faced with a patient with potentially
resectable stage IV disease, a careful assessment
of the patient’s medical condition, the extent
and biology of the cancer, and the feasibility
and risks of complete resection is necessary.
Many surgeons would approach these patients
with the idea of “looking for a reason not to
operate.” In other words, a thorough search
for metastatic disease should be undertaken
to be sure they do not have additional disease
elsewhere. This may include not only CT scan
and bone scan, but also PET scan. Although
the role of PET scanning in the diagnostic eval-
uation of breast cancer is evolving, this repre-
sents one situation in which it may be of
significant benefit. PET scanning appears to
be more sensitive than other imaging modal-
ities for the detection of distant metastatic dis-
ease (with the exception of brain secondary to
the high background activity of gray matter).
In many cases it is important not to proceed
with or exclude surgery based on imaging stud-
ies alone. Pulmonary nodules on CT may be
granulomatous disease. A solitary pulmonary
nodule may be a primary lung cancer rather
than a metastatic breast cancer, especially in a
smoker. An adnexal mass on a CT in a woman
with breast cancer is more likely to be of non-
breast origin than a breast cancer metastasis.
These may be benign or primary ovarian can-
cers. Although breast cancer is the second most
common cancer to metastasize to the adrenal
gland (lung is the first), many newly diagnosed
adrenal
masses
may
be
hyperplasia,
fatty
involvement,
or
nonfunctioning
adenomas.
Even an intracranial lesion may represent a
meningioma. FNAB, core-needle, or open biopsy
may be necessary to avoid misdiagnosis. PET
317
21—MANAGEMENT OF BREAST CANCER RECURRENCE

scans also have a significant false-positive rate,
and suspicious areas should be worked up with
more focused imaging and possible biopsy.
Once a thorough workup has been com-
pleted, several factors must be weighed when
considering whether resection is reasonable
(Box 21–6). The most significant issue is the
performance status of the patient and an esti-
mation of the relative risks of a planned opera-
tion.
Patients
with
significant
medical
comorbidities should be not be considered ideal
candidates for resection given the high rates of
postoperative morbidity and mortality. Patients
evaluated for lung resection should have a com-
plete pulmonary evaluation, whereas those
being considered for liver resection should have
relatively preserved liver function.
The best candidates for surgery are those with
single organ involvement. The overwhelming
majority of studies examining metastasectomy
for breast cancer are limited to patients with dis-
ease limited to one organ. Most oncologists con-
sider the presence of disease outside one organ to
be a contraindication to surgery. There are some
reports of resection in the presence of additional
disease, such as hepatic resection in the face of
both liver and bone disease, the argument being
that metastatic bone disease is more indolent
and has a more prolonged natural history. How-
ever, this situation should be limited to patients
who have well-controlled or stable disease.
Even better than single-organ disease are
patients with only one metastatic focus. Soli-
tary metastases appear to have a better out-
come after surgery than multiple metastases.
For example, patients undergoing resection of
a single lung metastasis appear to have a lon-
ger survival than patients undergoing resec-
tion of two or more lesions. This may be
related to biology but may also be representa-
tive of the ability to achieve a compete resec-
tion. This is particularly true in the setting of
hepatic metastases, in which the ability to
achieve a complete resection while retaining
a sufficient volume of functional liver and
the location of the lesions are probably more
important considerations. Bilobar disease or
location close to the porta hepatis is usually
considered a contraindication to resection.
Complete resection appears to be associated
with
a
significantly
better
outcome
than
incomplete in most series.
An important factor to consider is disease-
free survival (DFS). The interval between the
diagnosis of the primary breast cancer and the
development of distant disease is an important
prognostic indicator for any patient with meta-
static breast cancer, reflective of the underlying
biology of the disease. A longer disease-free
interval (DFI) is associated with a better out-
come after resection of all forms of metastatic
disease. What remains unclear is whether their
prolonged survival is secondary to the surgery
or whether they have more indolent disease
and would have survived just as long without
surgical intervention.
Another consideration is the postsurgery
systemic therapy options for the patient.
Although there is no clear evidence suggest-
ing a benefit to continuing systemic therapy
after metastasectomy, this is a frequent strat-
egy and is supported by some retrospective
series. Many series suggest that ER positivity
is associated with a better outcome after sur-
gery of stage IV disease, most likely as a
result of the benefit of ongoing endocrine
therapy.
Resection of Specific Metastatic
Sites
Lung Metastases
From 10% to 25% of patients with breast can-
cer that develop metastatic disease will have
disease that is limited to the lung. In many
cases, this will represent bilateral disease, pre-
cluding resection. However, for the patient
with a solitary pulmonary nodule, resection
should be strongly considered. One reason is
that more than 50% of single solid pulmonary
BOX 21–6 FACTORS WHEN
CONSIDERING RESECTION OF STAGE
IV DISEASE


Patient age


Comorbidities


Ability to tolerate resection


Likelihood of complete resection


Single-organ versus multiple-organ
disease


Solitary versus multiple lesions


Disease-free interval


Estrogen receptor/progesterone receptor
(ER/PR) status


Human epidermal growth factor receptor
2 (Her-2/neu) status


Options for postsurgical systemic
therapy
318
SURGICAL FOUNDATIONS: ESSENTIALS OF BREAST SURGERY

nodules in patients with a history of breast
cancer will be other types of tumors, such as
primary lung cancer, which may be amenable
to curative resection. Beyond that, there is
the potential for long-term survival. Pulmo-
nary metastasectomy provides an opportunity
for long-term survival in patients with stage
IV breast cancer. In retrospective series, 5-year
survival rates range from 31% to 80%, and
median survival durations are between 42
and 79 months. In the largest series of 467
patients derived from the International Regis-
try of Lung Metastases, survival rates were
38% and 20% after 5 and 15 years, respec-
tively. Long-term benefit from resection has
also been suggested in two nonrandomized
series comparing surgically treated patients
with those treated by other means. However,
in the absence of randomized trials, it is diffi-
cult to know for certain if these results are bet-
ter than could have been achieved without
surgery and whether the results are secondary
to selection bias. Patients may have not been
recommended surgery because of poor prog-
nostic signs (i.e., multiple metastases, short
DFI) or low performance status. Even for
patients with more than one nodule, resection
may be feasible. Based on the data from the
International Registry of Lung Metastases, the
prognosis of patients with pulmonary metas-
tases after pulmonary metastasectomy can be
stratified into four groups (Table 21–3).
Liver Metastases
The liver is involved in over one half of patients
with metastatic breast cancer, but it is rare to
find isolated liver disease (5% to 12% of stage
IV patients) and liver involvement is a poor
prognostic sign. With modern chemotherapy,
the median survival for patients with liver only
metastatic disease is approximately 22 to 27
months.
Although
the
resection
of
liver
metastases from colon cancer is common, the
resection of breast cancer metastases to the liver
is less common and more controversial. How-
ever, for patients who are appropriately selected,
liver resection may prolong survival to a greater
extent than standard nonsurgical therapies. In
retrospective series, 5-year survival rates for
resectable patients range from 18% to 59%.
Although the absence of randomized trials
makes it difficult to know with certainty that
these outcomes are better than can be achieved
with systemic therapy alone, the reported long-
term survival rates among selected patients
seem higher than can be achieved with chemo-
therapy alone.
The ideal candidate (albeit rare) has a soli-
tary metastasis, no evidence of extrahepatic
metastatic disease, normal liver function, a
good performance status, and a long DFI after
treatment of the primary tumor. An essential
part of the workup in patients who are consid-
ered for hepatectomy is precise imaging of the
liver with either helical CT or MRI and full
staging to rule out distant disease, possibly
with the use of PET scanning. If multiple
nodules can be resected, it may still be a con-
sideration, but bilobar disease should be con-
sidered a contraindication to resection. Initial
laparoscopic exploration may spare unresect-
able patients the morbidity of a laparotomy
because up to one half of patients even consid-
ered for resection are discovered to have dif-
fuse liver lesions or peritoneal dissemination
at the time of laparotomy.
Because of the limited number of patients
with isolated liver metastases who are candi-
dates for resection, other forms of liver-directed
therapy have been explored. The majority of
these are ablative techniques that were intro-
duced for the treatment of unresectable primary
hepatocellular cancer or colorectal metastases,
including percutaneous ethanol injection, cryo-
therapy, radiofrequency ablation (RFA), and
TABLE 21–3
International Registry of Lung Metastases Stratification of Patients
Undergoing Pulmonary Metastasectomy
Resection
Disease-Free
Survival
(Months)
Number of
Metastases
5-Year
Survival
Rate (%)
10-Year
Survival
Rate (%)
Median
Survival
(Months)
Group I
Complete
36
Solitary
50
26
59
Group II
Complete
<36
Solitary
35
21
36
Group III
Complete
<36
Multiple
13
13
2
Group IV
Incomplete
—
—
18
—
25
319
21—MANAGEMENT OF BREAST CANCER RECURRENCE

interstitial laser therapy. Because of its ease of
delivery and efficacy, RFA has evolved into the
treatment of choice for the ablation of meta-
static tumors involving the liver, including
breast cancer; it has largely replaced cryosurgical
ablation. RFA entails the local application of
radiofrequency thermal energy to a lesion, in
which a high frequency alternating current
moves from the tip of an electrode into the tis-
sue surrounding that electrode. As the ions
within the tissue attempt to follow the change
in the direction of the alternating current, their
movement results in frictional heating of the
tissue. As the temperature within the tissue
becomes elevated beyond 140 F (60 C), cells
begin to die, resulting in a region of necrosis sur-
rounding the electrode. Another potential use
for RFA is in patients who appear to have
isolated, potentially resectable liver metastases
as a temporizing maneuver while awaiting inter-
val reevaluation to ensure the absence of extra-
hepatic disease.
Brain Metastases
Although 10% to 16% of women with stage IV
breast cancer have brain involvement, making
it the second most common cause of brain
metastases, like liver metastases, brain metas-
tases typically occur late in the course of the dis-
ease and are rarely isolated. Brain metastases are
associated with a poor prognosis, with a median
survival (untreated) of only 1 to 2 months.
Whole brain radiation therapy (WBRT) provides
effective but brief palliation (symptoms return
within months) and increases median survival
to 4 to 6 months. Systemic chemotherapy may
provide similar benefits.
In the one third of patients with brain
metastases who have no evidence of extracra-
nial disease, a small subset will have solitary
brain metastases, and these patients may be
amenable to treatment. Surgical resection is
associated with improved outcomes relative
to WBRT alone and can provide rapid and
more durable symptom palliation. Uncon-
trolled series suggest median survival dura-
tions of 16 to 37 months can be achieved in
highly selected patients. Thus, surgical resec-
tion should be considered in selected patients
with solitary metastases without extracranial
disease. Surgery should only rarely be consid-
ered in patients with more than one brain
metastasis, except possibly if one large symp-
tomatic lesion predominates.
Over the last decade, stereotactic radiosurgery
(SRS) has emerged as an appealing alternative
to resection in patients with a limited number
of cerebral metastases. SRS combines the princi-
ple
of
stereotactic
localization
to
achieve
accurate targeting with multiple convergent
radiation beams of equal intensity to deliver a
high radiation dose to a well-defined area
within the brain. SRS has been used as a pri-
mary treatment for single or multiple lesions,
as a means of administering a local “boost” to
a brain metastasis after WBRT and also for sal-
vage therapy in patients who recur following
surgery or WBRT. Whether or not the results
with SRS are better than can be achieved with
resection is difficult to ascertain. Although
there is no question that SRS represents a rea-
sonable alternative to surgery for patients who
are not surgical candidates (because of location,
comorbidity), a randomized trial directly com-
paring both treatments has not been conducted.
In the absence of data from randomized trials,
the choice of SRS over surgery in patients with
solitary lesions is typically based on the size
and accessibility of the lesion, presence or
absence of symptoms, and the patient’s func-
tional status. Because the risk of neurotoxicity
and local failure is higher with larger lesions,
SRS is best reserved for lesions with a diameter
of 3 cm or less. Surgery offers the best potential
for immediate decompression of large solitary
symptomatic
lesions,
whereas
for
smaller
asymptomatic lesions, it is reasonable to con-
sider either surgery or SRS.
Bone Metastases
Bone is the most common site of metastatic
involvement in breast cancer, and in compari-
son to other sites of spread, is typically charac-
terized
by
an
indolent
course
and
good
response to endocrine maneuvers. In approxi-
mately 20% of cases, bone metastases are soli-
tary, and in such cases, radiation therapy can
provide effective pain relief and prevent frac-
ture. RFA has also been used to treat painful
individual bone. Given the relative effective-
ness of systemic therapy and radiation or RFA,
there is a limited role for resection as a curative
option for the majority of bone metastases.
Surgery is used for the palliative treatment of
epidural spinal cord or nerve compression syn-
dromes and to reduce or prevent bone metasta-
sis-associated
fractures.
One
exception
in
which a curative resection of a bone metastases
may be indicated is in the sternum.
For the rare situation where bone involve-
ment is limited to the sternum, potentially
curative surgical resection may be considered.
320
SURGICAL FOUNDATIONS: ESSENTIALS OF BREAST SURGERY

Isolated sternal involvement may be meta-
static disease, but it may also represent locore-
gional recurrence from the breast or internal
mammary nodes. Also, possibly because there
is no communication with the paravertebral
venous plexus through which cancer cells
can spread to other bones, sternal metastases
may remain solitary for a long time. Sternal
resection can provide optimal local control,
palliate thoracic pain, prevent the complica-
tions associated with progressive sternal dis-
ease, and may be associated with prolonged
relapse-free survival.
Breast Surgery in the Face of Stage
IV Disease
Approximately 3% of women with newly diag-
nosed breast cancer have metastatic disease at
the time of presentation. Until recently, the
general rule was that there was no indication
for breast surgery in this setting unless it was
needed for palliative purposes. This was based
on the idea that once metastatic disease is
present, aggressive local therapy would have
no impact on outcome. Other than a biopsy
to confirm the diagnosis and perform immu-
nohistochemical staining, the breast tumor
was left in place and monitored as a measure
of response to therapy.
Several retrospective reviews have raised the
possibility that breast surgery in the presence
of known metatstatic disease may improve sur-
vival. These range from single institution
reviews to large database studies. Across these
studies, a consistent improvement in survival
is seen in the women who had complete resec-
tion of their primary tumor. This holds even
when the analysis is adjusted for age, nature
of the metastatic disease and the use of sys-
temic therapy. Several biologic theories have
been proposed, including the idea that surgery
prevents continued dissemination of disease
from the primary, increases immune recogni-
tion or removed growth factors produced by
the primary that influence distant metastases.
However, there are other explanations for this
as well. It is possible that many of the patients
who had excellent outcomes after surgery in
the face of stage IV disease were actually incor-
rectly classified (e.g. a CT showing what were
thought to be pulmonary metastases were
actually benign). The more likely explanation
is that these retrospective studies reflect a sig-
nificant selection bias. Patients who are youn-
ger, healthier and have more controllable
disease are selected for surgery while patients
expected to have a lower survival are not
offered surgery. Many patients receive chemo-
therapy first in this setting, and so surgery
may
be
reserved
for
those
with
a
good
response to systemic therapy.
Only a randomized trial will answer whether
routine resection of the primary tumor in the
face of metastatic disease can impact survival,
and while this trial faces significant hurdles,
it is being planned. Until then, when faced
with this situation, the surgeon must weigh
several factors in deciding whether to offer
the stage IV patient primary breast surgery.
These include their age and co-morbidities,
the surgery that would be necessary for control
(lumpectomy vs. mastectomy), the predicted
response to systemic therapy (size,
grade,
nodal status, ER, PR and Her-2/neu status) or
the demonstrated response to systemic ther-
apy, the number and sites of the metastases
(single vs. multiple, bone-only vs. visceral),
and the palliative benefit of resection. Primary
breast surgery may be appropriate in selected
patients with metastatic disease.
Principles of Systemic Therapy
for Metastatic Breast Cancer
Althougha subset of patientswithstage IV breast
cancer may benefit from surgery, this reflects a
small number of patients even when a liberal
use of surgery in stage IV disease is applied. The
management of metastatic breast cancer is pri-
marily systemic and is not considered curative.
The goals of treating patients with stage IV can-
cer are to prolong survival, particularly symp-
tom-free survival, thus improving quality of life
(Box 21–7). The goal of the medical oncologist
is to balance the symptoms caused by the cancer
versus the symptoms caused by the systemic
therapies. This is complex because the natural
history of advanced breast cancer can be quite
prolonged and treatment may involve multiple
regimens of chemotherapy, which are con-
stantly adjusted based on tumor response and
patient symptoms.
BOX 21–7 GOALS OF SYSTEMIC
THERAPY IN STAGE IV DISEASE


Prolong survival


Alleviate symptoms


Prevent tumor-related complications


Improve quality of life
321
21—MANAGEMENT OF BREAST CANCER RECURRENCE

When patients are first diagnosed with stage
IV breast cancer, a thorough staging must be
performed to delineate the extent of disease,
and a detailed history and physical examina-
tion are performed looking to evaluate the
patient’s present symptoms and quality of life.
A biopsy of a metastatic lesion should be con-
sidered not only to document true stage IV dis-
ease (as compared with a false-positive study)
but also to see if the cancer is hormone-receptor
positive and Her-2/neu positive. The decision to
initiate therapy is then based on both the his-
tory and the tumor biology. Patients with mini-
mal symptoms and hormone sensitive tumors
are usually begun on endocrine therapy. There
is no survival advantage to starting chemother-
apy or combined chemotherapy/endocrine ther-
apy at this point as compared with endocrine
therapy alone.
For patients who have hormone-receptor-
negative disease or have tumors that are refrac-
tory to hormonal therapy, chemotherapy is
considered. This is not mandatory because
patients
with
minimal
symptoms
may
be
observed. However, patients with tumor-related
symptoms or have a heavy tumor burden (par-
ticularly visceral disease) are given chemother-
apy. Patients with significant symptoms or in
visceral crisis are started on chemotherapy in
combination with endocrine therapy if they
are hormone sensitive. Patients overexpressing
Her-2/neu are generally started on Herceptin.
The likelihood of responding to chemother-
apy depends on several factors, including the
tumor biology, the DFI since initial treatment,
whether adjuvant chemotherapy was used and
what agents, the number of regimens they
have already received for their stage IV disease,
and the sites of the disease. When the disease
progresses in the face of treatment, the regi-
men is typically changed. Sometimes, patients
who have had extended periods of response or
stable
disease
may
be
taken
off
therapy
(“chemo holiday”). The likelihood of response
and duration of response tends to be greatest
with first-line chemotherapy and decreases
with each subsequent line of treatment.
The median survival for patients with stage
IV breast cancer is typically 2 to 3 years but this
is widely variable and a large number of
patients (as high as 20%) may live for many
years. Although there is no randomized data
comparing chemotherapy to no treatment, the
retrospective data would suggest that survival
is prolonged in patients being treated because
patients who respond tend to live longer than
those who do not. However, although survival
may be prolonged, it is important that patients
understand that cure is highly unlikely.
At some point, the cancer will no longer
respond to treatment and the side effects of
the therapy start to outweigh the benefits. Par-
ticipation
in
clinical
trials
of
new
agents
remains an option at this point and is generally
strongly encouraged, although patients should
be counseled that these trials are unlikely to sig-
nificantly alter the course of the disease. Even-
tually,
and
this
point
is
different
for
all
patients, purely palliative or “best supportive
care” may be the most appropriate choice.
Suggested Readings
1. Clemons M, Danson S, Hamilton T, et al. Locore-
gionally recurrent breast cancer: incidence, risk fac-
tors and survival. Cancer Treat Rev 2001;27:67–82.
2. Easson AM, McCready DR. Management of local
recurrence of breast cancer. Expert Rev Anticancer
Ther 2004;4(2):219–226.
3. Newman EA, Cimmino VM, Sabel MS, et al. Lymphatic
mapping
and
sentinel
lymph
node
biopsy
for
patients with local recurrence afterbreast-conservation
therapy. Ann Surg Oncol 2006;13(1):52–57
4. Wright FC, Walker J, Law L, et al. Outcomes after
localized axillary node recurrence in breast cancer.
Ann Surg Oncol 2003;10:1054–1058.
322
SURGICAL FOUNDATIONS: ESSENTIALS OF BREAST SURGERY

22
Breast Cancer in Special
Populations
MALE BREAST CANCER
Clinical Presentation and
Workup
Treatment
Adjuvant Systemic Therapy
BREAST CANCER IN PREGNANCY
Effect of Pregnancy on Breast
Cancer
Diagnosis of Breast Cancer in
Pregnant Women
Staging
Treatment
BREAST CANCER IN OLDER
PATIENTS
BREAST CANCER AMONG
AFRICAN AMERICAN WOMEN
BREAST CANCER AMONG
OTHER ETHNICITIES
Breast Cancer in Special Populations: Key Points
Understand the incidence and risk factors for male breast cancer.
Know the surgical and adjuvant treatment for male breast cancer.
Describe your approach to the patient who is pregnant presenting with breast
cancer.
Know when pregnancy is and is not a contraindication to imaging, surgery
and anesthesia, radiation therapy, chemotherapy, or hormonal therapy.
Understand how age may impact decisions in breast cancer treatment.
Know the disparities that exist between African American and Anglo
American women and the possible explanations.
Understand the differences in presentation, histology, and stage of breast
cancer among African Americans compared with Anglo Americans.
323

Male Breast Cancer
Although breast cancer is the most common
malignancy among women, it is extremely rare
among men. In 2008, there were an estimated
1990 new cases of male breast cancer, which
represents only 1% of all breast cancer cases
and 450 deaths. Male breast cancer shares many
of the same characteristics with female breast
cancer, although there are some stark differ-
ences. The median age of onset of male breast
cancer is 66, approximately 10 years older than
for females. Several risk factors have been identi-
fied for breast cancer in men (Box 22–1). Many
of these are related to alterations in estrogen/
androgen balance because androgens appear
to have a protective effect on breast tissue by
inhibiting cell proliferation. However, the rela-
tionship between hormones and male breast
cancer is not clear because men with breast can-
cer do not exhibit abnormalities in peripherally
detectable hormone levels. In addition, other
conditions that result in increased estrogen,
such as obesity, thyroid disease, marijuana use,
or exogenous estrogen use do not seem to
increase the risk of breast cancer.
A family history of breast cancer is present in
approximately 15% to 20% of cases. Breast can-
cer gene (BRCA) 2 mutations are associated
with a 6% lifetime risk of male breast cancer,
which might not sound high compared to the
risk in females, but represents a 100-fold higher
risk compared to the general population. BRCA2
mutations are responsible for between 5% and
15% of male breast cancers. BRCA1 mutations
do not have as significant a role. Male breast
cancers in BRCA2 carriers may exhibit a more
aggressive phenotype, with higher grade and
overexpression of human epidermal growth fac-
tor receptor 2 (Her-2/neu). A mutation in the
tumor suppressor gene PTEN, which is asso-
ciated with Cowden syndrome, or the mismatch
repair gene hMLH1 have also been reported in
patients with male breast cancer, although
whether or not there is a causal relationship
remains unclear.
Clinical Presentation and Workup
The typical presentation of male breast cancer
is that of a painless, firm subareolar mass. Less
commonly, it may present as a mass in the
upper, outer quadrant. Because there is mini-
mal breast tissue, the nipple is commonly
involved (ulceration, retraction) although nip-
ple discharge is rare. The mass may be fixed to
the overlying skin or underlying muscle. The
differential diagnosis would include gyneco-
mastia, infection (abscess), or a nonbreast pri-
mary such as sarcoma.
Mammogram is helpful, being abnormal in
80% to 90% of cases, and can help differenti-
ation between gynecomastia and breast can-
cer. However, false-negatives do occur and so
a tissue diagnosis is warranted for any suspi-
cious mass in the breast. This should be
either a core biopsy or open biopsy because
fine-needle aspiration (FNA) can be inaccu-
rate. Invasive ductal carcinoma represents
more than 90% of cases; invasive lobular is
rare. Ductal carcinoma in situ (DCIS) is also
rare in men. Over 90% of male breast cancers
express estrogen receptor (ER) and progesterone
receptor (PR). The her-2/neu protooncogene is
less likely to be overexpressed in men than in
women. Staging workup is similar to that of
female breast cancer. A full history and physical
should be performed looking for signs or symp-
toms of metastatic disease. Ultrasound of the
breast and axilla are often performed because
sentinel lymph node (SLN) biopsy can be
avoided if an ultrasound-guided FNA can docu-
ment nodal metastases preoperatively. Com-
puted tomography (CT) scan and bone scan
should be obtained if the patient has signs or
symptoms suggestive of metastatic disease.
Treatment
Localized male breast cancer is treated by mas-
tectomy. Radical mastectomy should not be
necessary unless there is extensive chest wall
involvement. Given the lack of breast tissue
BOX 22–1 RISK FACTORS FOR
MALE BREAST CANCER
Gynecomastia or previous benign
breast disease
Jewish ancestry
Family history of breast cancer
Previous chest wall irradiation
Testicular disease (orchitis,
cryptorchidism, congenital inguinal
hernia, infertility, orchiectomy, injury)
Liver disease (cirrhosis, alcoholic liver
disease, schistosomiasis)
Klinefelter syndrome
Prolactinoma
Breast cancer gene (BRCA) 2 mutation
Cowden syndrome (PTEN mutation)
324
SURGICAL FOUNDATIONS: ESSENTIALS OF BREAST SURGERY

and central location of the tumors, breast-
conserving therapy (BCT) is not typically con-
sidered. Radiation is typically not recommended
after mastectomy, although recommendations
have been made to use postmastectomy radia-
tion therapy for the same indications you would
use in women (locally advanced disease or mul-
tiple positive axillary nodes) to decrease the like-
lihood of locoregional recurrence.
The management of the axilla has changed
with the advent of SLN biopsy. Although mod-
ified radical mastectomy has been the stan-
dard, SLN has been shown to be successful in
men as well and may spare the morbidity of
axillary lymph node dissection (ALND) for
patients who are node negative. Patients with
a positive sentinel node should have a com-
plete lymph node dissection. As with female
breast cancer, the number of positive nodes
correlates with survival. Patients with histolog-
ically negative nodes have a 10-year disease-
specific survival between 77% and 84%. This
drops to around 50% with one to three posi-
tive nodes and 14% to 24% for four or more
positive nodes (Table 22–1).
Adjuvant Systemic Therapy
The recommendation for adjuvant therapy is
based largely on the benefits seen in women
and small retrospective reports (compared to
historical controls) because breast cancer in
men is too uncommon to perform randomized
trials. Because the majority of cases are hormone-
receptor positive, 5 years of adjuvant tamoxi-
fen is frequently recommended. However, men
have more difficulty than women tolerating
the side effects and may not last the full 5 years
(Box 22–2). Chemotherapy is also typically
recommended for men at high risk of recur-
rence as it is in women, although chemotherapy
appears to be used less often in men when com-
pared stage by stage. The indications are the
same as for women, node-positive disease or
tumor size greater than 1 cm. Chemotherapy
should also be considered for men with hor-
mone-receptor-negative disease. Her-2/neu and
p53 expression have been associated with poor
prognosis and may push toward more aggressive
systemic therapy. The choice of agents is also
similar to women, with anthracycline-based che-
motherapy for patients who are node negative,
and anthracyclines and taxanes for patients
who are node positive.
With adequate therapy, the 5-year survival by
American Joint Committee on Cancer (AJCC)
tumor stage is between 80% and 100% for stage
I disease, 65% to 80% for stage II disease, 25%
to 60% for stage III disease, and between 0%
and 25% for stage IV disease. Although in the
past breast cancer was considered more aggres-
sive in men than in women, the most recent
data suggests that when matched for stage and
grade, there is not a significant difference in
outcome between genders.
In patients with metastatic disease, if they are
still receptor positive, hormone therapy should
be considered the first-line treatment with sys-
temic chemotherapy reserved for second-line
treatment. Hormone therapy can be medical
(tamoxifen, megestrol acetate, androgens, ster-
oids) or surgical (orchiectomy, adrenalectomy,
TABLE 22–1
Disease-Specific and Overall Survival Rates in Male Breast Cancer
From 1,986 Patients in the Surveillance, Epidemiology and End Results Database,
1988–2001
Stage I
Stage II
Stage III
Stage IV
Disease-specific survival (%)
5 year
96
88
60
23
10 year
93
74
44
21
Overall survival (%)
5 year
78
66
39
14
10 year
55
39
21
5
From Giordano SH. A review of the diagnosis and management of male breast cancer. The Oncologist
2005;10:471-479.
BOX 22–2 SIDE EFFECTS OF
TAMOXIFEN IN MEN
Decreased libido
Weight gain
Hot flashes
Mood alteration
Depression
325
22—BREAST CANCER IN SPECIAL POPULATIONS

or hypophysectomy). For patients who are ER
positive, tamoxifen has a higher response rate
than the other therapies with a better side-effect
profile. In patients who progress following
tamoxifen treatment, these alternative endo-
crine therapies should be considered. Although
bilateral orchiectomy is effective, many men
are unwilling to opt for this. The role of aroma-
tase inhibitors (AIs) is unclear. Chemotherapy
should be used in patients who are ER negative
or patients who are ER positive and not respond-
ing to hormonal therapy.
Breast Cancer in Pregnancy
A challenging and not infrequent dilemma is
the management of breast cancer in pregnant
women. Breast cancer is the second most com-
mon cancer associated with pregnancy (cervical
cancer is first) with an incidence of approxi-
mately 1 in 3000 pregnancies. The incidence of
pregnancy-associated breast cancer is likely to
increase as more women delay childbearing
given the increased incidence of breast cancer
with increasing age.
Effect of Pregnancy on Breast
Cancer
The
relationship
between
pregnancy
and
breast cancer risk is complex. Overall, a youn-
ger age at first live birth is associated with a
lifetime risk of breast cancer. Having a preg-
nancy before age 20 reduces lifetime risk by
approximately 50%. However, although there
may be a long-term protective effect on the
development of breast cancer with pregnancy,
pregnancy itself may result in a transient
increase in risk. Two population based studies
have demonstrated an increased risk of breast
cancer for 3 to 15 years after pregnancy fol-
lowed by a subsequent decline. This transient
risk appears to be most apparent among
women who are older at the time of their first
delivery. How can this be? Although it is not
exactly known, it may be that the hormones
associated with pregnancy can stimulate the
growth of cells in the early stages of malignant
transformation and may also induce the differ-
entiation of normal mammary stem cells that
would have had the potential for neoplastic
change in the future. Therefore, premenopau-
sal
women
who
have
early
premalignant
changes (more likely among older premeno-
pausal women) may see pregnancy accelerate
that transformation. The remainder of women
lose a portion of those undifferentiated cells
that may ultimately become breast cancer,
decreasing their long-term risk (Chapter 1).
Diagnosis of Breast Cancer
in Pregnant Women
Delay in diagnosis contributes significantly to
the worse outcome typically associated with
breast cancer during pregnancy. As with non-
pregnant women, the typical presentation is a
mass in the breast, but the physiologic changes
(engorgement, hypertrophy) may delay both
the patient and physician from detecting a
mass. It is not uncommon for physicians to
assume the mass is benign or delay biopsy until
after pregnancy, but even a 1 month delay in
diagnosis can increase the risk of nodal involve-
ment. Therefore, the index of suspicion must be
high for any pregnant or postpartum woman
presenting with a palpable mass. Mammogra-
phy can be performed safely in pregnant
women with abdominal shielding. Although
the use of mammography is hampered by the
increased water content, higher density, and
loss of fat in the breast during pregnancy, it
can still be useful. A negative mammogram,
however, should not dissuade your suspicion
because false-negative mammograms are not
uncommon. Ultrasound can be particularly
helpful for differentiating cystic from solid
lesions. Magnetic resonance imaging (MRI) is
possible because it is used for fetal imaging dur-
ing pregnancy with no suggestion of adverse
sequelae on the fetus, although the data on the
effectiveness on MRI of the breast during preg-
nancy is lacking. In addition, gadolinium con-
trast, which is often used to differentiate
benign from malignant lesions in breast MRI,
crosses the placenta and causes developmental
abnormalities in animal models.
There is no excuse not to biopsy a clinically
suspicious mass in a pregnant female. Fine-
needle aspiration (FNA) is more difficult to inter-
pret, but in the hands of a skilled cytopathologist
(who knows the specimen comes from a preg-
nant woman) it can be accurate. Core biopsy
can be safely performed under local anesthesia,
and although milk fistula has been described, it
is extremely rare. Both incisional and excisional
biopsy can also be performed safely.
Staging
Women with pregnancy-associated breast can-
cer tend to present with worse prognostic signs
(ER/PR negative, high grade) and more advanced
326
SURGICAL FOUNDATIONS: ESSENTIALS OF BREAST SURGERY

stage than nonpregnant women (larger tumors,
higher frequency of nodal or distant metastases).
It is unclear if this is more related to delay in
diagnosis than a more aggressive biology. It
is also unclear if, when controlling for all prog-
nostic factors, breast cancer during pregnancy
has a worse outcome. It is important, however,
to accurately stage the patient when planning
therapy. The initial staging examination should
be similar to that in nonpregnant women, with
a thorough history and physical. Ultrasound
of the axilla with FNA of any clinically suspi-
cious nodes should be considered. The indica-
tions for a complete staging workup are the
same as in nonpregnant women, reserved for
women with clinical positive nodes, T3 or
T4 tumors, or symptoms suggesting distant
disease.
Computed
tomography
(CT)
scans
should be avoided during pregnancy because of
the large cumulative radiation dose. Chest
x-ray is safe with abdominal shielding, although
limited in visualizing the lower lung paren-
chyma late in gestation. The liver should be eval-
uated with an abdominal ultrasound. MRI can
be used for further evaluation if necessary. Bone
scans can also be obtained during pregnancy if
necessary, however the patient should be ade-
quately hydrated and have a Foley catheter for
8 hours to prevent retention of radioactivity in
the fetus.
Treatment
As with nonpregnant women, the goal of ther-
apy is both the local and systemic control of dis-
ease (Fig. 22–1). The impact of those treatments
on the fetus must be strongly considered.
Treatment should be coordinated with a special-
ist in maternal and fetal medicine to monitor
the pregnancy. The gestational age and expected
Pregnant patient with breast cancer
Rule Out Distant Disease
If needed:
No evidence of distant spread
1st
trimester
Strongly
desires BCT
2nd or early 3rd
trimester
Consider
therapeutic
abortion
Mastectomy
SLN (radiotracer only)
or ALND
Chemotherapy
not clearly
indicated
Chemotherapy
clearly indicated
Late 3rd
trimester
Preoperative
chemotherapy
Mastectomy or
lumpectomy
SLN (radiotracer only)
or ALND
Delivery would
precede XRT
XRT would
precede delivery
Mastectomy
SLN (radiotracer only)
or ALND
Adjuvant chemotherapy if indicated
Radiation therapy and/or hormonal therapy after
delivery, if necessary
Radiation therapy and/or
hormonal therapy after
delivery, if necessary
Mastectomy or lumpectomy
ALND
Adjuvant chemotherapy,
radiation therapy and/or
hormonal therapy after
delivery
Mastectomy or Lumpectomy
SLN (radiotracer only)
or ALND
Figure 22–1. Approach to the pregnant patient with breast cancer. The primary goal is to avoid radiation
while the patient is pregnant and a long treatment-free delay between surgery and radiation. Chemotherapy
may be used but only based on the risk of systemic disease and not to provide a bridge to radiation that allows
breast-conserving therapy.
327
22—BREAST CANCER IN SPECIAL POPULATIONS

date of delivery will be important pieces of infor-
mation in planning therapy. Amniocentesis
may be necessary to determine pulmonary
maturity.
When pregnant women are diagnosed with
breast cancer, one option is to terminate the
pregnancy. However, breast cancer can be suc-
cessfully treated during pregnancy, and early
termination does not improve the outcome
of the breast cancer.
Surgery can be performed safely in pregnant
women when planned with both anesthesiol-
ogy and obstetrics (Box 22–3). Therefore, there
is no contraindication to performing a modi-
fied radical mastectomy (MRM) in a pregnant
woman. However, pregnant women are often
just as motivated to conserve the breast and
avoid ALND as nonpregnant women. Unfortu-
nately, radiation therapy to the breast, an
important component of BCT, is contraindi-
cated during pregnancy. The risk to the fetus
is
high
because
it
cannot
be
adequately
shielded. If a woman wishes to pursue breast
conservation, she has several options.
If the cancer is detected in the third trimester,
or the late second trimester, she may undergo
lumpectomy and defer the radiation until after
delivery. If, based on the stage of the cancer,
she will require systemic chemotherapy, this
will delay the implementation of radiation
therapy up to 6 months. This may allow
women in the first or second trimester to opt
for breast conservation. Neoadjuvant chemo-
therapy can also be considered when appropri-
ate. This results in a catch 22 because women
who have smaller cancers early in the preg-
nancy will more often require mastectomy
because they do not require adjuvant chemo-
therapy and thus would have an unacceptable
delay
between
lumpectomy
and
radiation.
Women in this situation may consider this
option; however, they may be exposing them-
selves to a higher local recurrence rate.
Pregnant women who are clinically node
negative may undergo SLN biopsy for axillary
staging. The procedure should be done with
radiolabelled colloid only and not isosulfan
blue dye secondary to the risk of allergic reac-
tion. The radiolabelled colloids are associated
with a minimal dose of radiation exposure to
the fetus as a result of the rapid uptake in the
maternal reticuloendothelial system.
Although there are increased risks, adjuvant
chemotherapy can be administered to preg-
nant women with breast cancer (Box 22–4).
Potential agents include cyclophosphamide,
doxorubicin, and 5-Fluorouracil (5-FU). Meth-
otrexate
is
contraindicated.
Chemotherapy
should not be administered during the first tri-
mester because there is an increased risk of
abortion and malformations. Beyond the first
BOX 22–3 ANESTHETIC CONCERNS
IN THE PREGNANT PATIENT
Altered physiology of pregnancy


Increased blood volume with physiologic
anemia


Increased heart rate and cardiac output


Elevated diaphragm, decreased
functional residual capacity


Increased oxygen consumption


Decreased partial pressure of carbon
dioxide (pCO2), decreased buffer base
capacity, and normal acid-base balance
(pH)


Increased fibrinogen and platelet count
Prolonged gastric emptying and
increased risk of aspiration


Use of oral noncolloidal antacids and
Reglan


Rapid sequence induction with cricoid
pressure


Hypotension resulting from aortocaval
compression


Left lateral tilt with 15-degree wedge
under right hip
Maternal hyperventilation and fetal
acidosis


Monitor fetal heart rate, avoid
hyperventilation, and maintain normal pH
Risk of preterm labor
BOX 22–4 RISKS OF
CHEMOTHERAPY ON THE FETUS
AND NEONATE
Immediate risks
Spontaneous abortion
Teratogenesis
Premature birth or low birth weight
Possible complications secondary to in
utero exposure
Carcinogenesis
Sterility
Delayed physical or mental growth
Mutation
328
SURGICAL FOUNDATIONS: ESSENTIALS OF BREAST SURGERY

trimester, chemotherapy does not appear to
increase the risk of fetal abnormalities. The
optimal timing would have chemotherapy
conclude 4 weeks before delivery, so that
decreased blood counts do not lead to bleeding
or infectious complications. However, a careful
discussion needs to be held with the patient
regarding the risks and benefits of adjuvant
chemotherapy. Adjuvant chemotherapy may
be associated with intrauterine growth restric-
tion and prematurity. In addition, there is little
long-term data on children exposed to chemo-
therapy in utero. Endocrine therapy, particu-
larly
tamoxifen,
is
contraindicated
during
pregnancy. Postpartum tamoxifen can be con-
sidered
for
use
in
hormone-receptor-
positive tumors.
Breast Cancer in Older
Patients
The current median age at diagnosis for breast
cancer is 61, and most of the women who die
of breast cancerare over the age of 65. As the pop-
ulation grows and ages, new breast cancer cases
increase as the incidence of breast cancer rises
with age. It is therefore not surprising that an
individual surgeon’s practice will continue to
see an increasing percentage of breast cancer
patients in their 70s and 80s. It is therefore im-
portant to understand how to approach the
elderly woman with breast cancer, knowing
when age should factor into surgical decision
making and when it should not.
When compared to their younger counter-
parts, breast cancers in older women tend to
have different biologic characteristics. Breast
cancers in older women are more often of a
lower grade, are ER/PR positive, and associated
with a decreased expression of poor prognostic
markers such as Her-2/neu. They are also less
likely to involve the regional nodes. Despite
the fact that older women are often treated less
aggressively, their prognosis is good. In a study
of tumor biology and outcome from the Surveil-
lance, Epidemiology and End Results (SEER)
database, women over 70 with node-negative
tumors had an 8-year overall survival rate com-
parable to an age-matched population without
breast
cancer.
Women
with
node-positive
tumors had only a modest decrease in overall
survival. This is despite the fact that older
women had lower rates of surgery, radiation,
and
chemotherapy
than
younger
patients.
Although this would imply that breast cancers
in older women have a more indolent course,
that statement is certainly controversial and
could lead to undertreatment of the elderly pop-
ulation, resulting in excessive local, regional,
and distant recurrence.
Certainly, when looking at the older popula-
tion as a whole, there is a decreased overall sur-
vival and an increased risk of death from
causes other than breast cancer, and this must
be taken into account when reviewing treat-
ment options. However, the clinician must also
take into account that overall patients are living
longer, thus a healthy older patient may have a
longer period to develop recurrence than just
10 years ago. It is therefore not correct to say
that simply because a patient is over 70 or 75 it
is reasonable to offer less aggressive therapies.
Instead, when facing an individual elderly
patient with breast cancer, their chronologic
age should be secondary, and their physiologic
age should be examined. This would include
looking at their functional status, comorbidities,
and life expectancy. In this manner, the risks
and benefits of surgery and adjuvant therapy
can be more accurately weighed. There are sev-
eral tools that may be useful in this situation.
The
Eastern
Cooperative
Oncology
Group
(ECOG) and Karnofsky performance scales are
often used to identify patients with decreased
functional status and hence worse outcomes
with therapy (Tables 22–2 and 22–3). The com-
prehensive geriatric assessment (CGA) is a
structured evaluation of elderly patients on mul-
tiple levels including physical and functional
status, comorbidities, nutritional status, and
TABLE 22–2
Eastern Cooperative
Oncology Group (ECOG) Performance
Status Criteria
Grade
Status
0
Fully active, able to carry on all predisease
performance without restriction
1
Restricted in physically strenuous activity
but ambulatory and able to carry out
work of a light or sedentary nature (e.g.,
light housework, office work)
2
Ambulatory and capable of all self-care
but unable to carry out any work
activities; up and about more than 50%
of waking hours
3
Capable of only limited self-care;
confined to bed or chair more than 50%
of waking hours
4
Completely disabled; cannot carry on any
self-care; totally confined to bed or chair
5
Dead
329
22—BREAST CANCER IN SPECIAL POPULATIONS

geriatric
syndromes
such
as
dementia
or
depression. It may also be useful to assess these
patients in a multidisciplinary or tumor board
setting, to gain the input of medical oncolo-
gists
and
radiation
oncologists
before
planning surgical therapy.
If your assessment of the elderly patients
reveals a healthy woman with minimal func-
tional limitations, then the surgical options
are no different than the younger patient. Pri-
mary surgery can be either mastectomy or
BCT. Morbidity and mortality rates of mastec-
tomy in older patients are comparable to youn-
ger patients, although there is clearly some
selection bias. It is important to remember that
age is not a contraindication to BCT. Although
some studies demonstrate that older women
have lower rates of breast conservation, when
older women are presented with both options
they are just as likely to prefer breast conserva-
tion as younger women. To assume an older
woman cares less about body image and the
psychosocial
implications
of
mastectomy
would be incorrect, and surgeons should offer
the two surgical options in the same manner
as they would a younger woman.
For
elderly
women
with
larger
primary
tumors who still desire breast conservation,
neoadjuvant therapy also remains an option.
If there is a concern regarding neoadjuvant che-
motherapy in this population, an alternative
approach might
be
neoadjuvant hormonal
therapy. In older patients who are hormone-
receptor positive, neoadjuvant hormonal ther-
apy with tamoxifen, anastrozole, or letrozole
have been reported to have clinical response
rates similar to those seen for chemotherapy.
The same recommendation should be made
for axillary evaluation. It has been suggested
that because older women are less likely to
be node positive and have decreased overall
survival, that axillary evaluation with SLN
biopsy may not be necessary. However, know-
ing whether an elderly patient is node posi-
tive
or
node
negative
may
significantly
change recommendations for adjuvant ther-
apy, and SLN biopsy has few side effects in
older women. This is an example in which
the multidisciplinary approach is quite useful
because the medical oncologist can weigh in
on whether systemic therapy might change
with the information gleaned from a SLN
biopsy.
A more controversial issue is the manage-
ment of the elderly patient with the positive
SLN. Although the standard of care is a com-
plete ALND, the overall survival benefit of
the
complete
ALND
is
unknown
for
all
patients with breast cancer, let alone older
patients, and older women tend to have worse
quality of life scores and difficulties with func-
tion after ALND. However, even in the absence
of an overall survival benefit, there may be a
benefit to regional control. Predictive models
and nomograms can help assess an individual
woman’s risk of harboring additional disease
in the nonsentinel lymph nodes, and this
information can be used for a balanced discus-
sion with the patient regarding the relative
pros and cons of completing the ALND in the
elderly patient with breast cancer who is SLN
positive.
Another area of discussion is whether radia-
tion is a necessary adjunct to lumpectomy
among older women. Radiation therapy is well
tolerated in elderly patients, and there is no
doubt that radiation will decrease in-breast
recurrences after lumpectomy and chest wall
recurrences
after
mastectomy.
Overall,
the
decreased local recurrence rates associated with
radiation will impact overall survival (see
Chapter 15), although most of these trials had
upper age cutoffs. Therefore, there has been
some question to the benefit of radiation ther-
apy in the elderly population. Two randomized
TABLE 22–3
Karnofsky Performance
Status
Grade
Karnofsky Scale
100
Normal, no complaints; no evidence of
disease
90
Able to carry on normal activity; minor
signs or symptoms of disease
80
Normal activity with effort; some signs or
symptoms of disease
70
Cares for self but unable to carry on
normal activity or to do active work
60
Requires occasional assistance but is able
to care for most personal needs
50
Requires considerable assistance and
frequent medical care
40
Disabled; requires special care and
assistance
30
Severely disabled; hospitalization is
indicated, although death is not
imminent
20
Very ill; hospitalization and active
supportive care are necessary
10
Moribund
0
Dead
330
SURGICAL FOUNDATIONS: ESSENTIALS OF BREAST SURGERY

studies addressed this issue. In a randomized
trial of radiation therapy compared to no radia-
tion therapy in 796 patients over the age of 50,
radiation had no impact on overall survival but
did decrease local recurrence rates from 7.7% to
0.6% (p < 0.001). In a study limited to women
who were hormone-receptor positive over the
age of 70, radiation decreased locoregional
recurrence from 4% to 1% (p < 0.001) but again
had no impact on distant disease-free or overall
survival. It may, therefore, be reasonable to
offer lumpectomy alone to a subset of older
women, omitting radiation therapy. This deci-
sion should be based on multiple factors
including the woman’s life expectancy, func-
tional status, ability to go through radiation,
tumor size, hormonal status, and lymph node
status. Again, the tumor board approach is par-
ticularly helpful and may impact the surgical
decision making if lumpectomy alone is a
consideration.
When faced with an elderly patient with
moderate to significant comorbidities, it can
sometimes be difficult to judge how aggressive
to be in managing their breast cancer. In
patients who are not good candidates for sur-
gery, hormonal therapy alone is often used if
the patient is hormone-receptor positive. In
randomized trials of primary endocrine ther-
apy versus surgery, overall survival is similar,
however, locoregional control is significantly
worse. Even among patients with advancing
age and comorbidities, both lumpectomy and
mastectomy
are
well
tolerated
and
many
patients treated with hormone therapy alone
will ultimately require surgery for local con-
trol. They may end up being worse candidates
for surgery when that time comes. Therefore,
endocrine therapy alone should be reserved
for patients with significant comorbidities for
whom surgery would carry excessively high
risks.
Finally, the most controversial aspect of breast
cancer care among the elderly is the use of sys-
temic adjuvant therapy. The benefits of adjuvant
therapy
for
breast-cancer-specific
prognosis
must be weighed against the treatment related
toxicity and the nonbreast-cancer prognosis.
Clinical trial data is limited as many prospective,
randomized trials failed to accrue significant
numbers of elderly patients. The Early Breast
Cancer Trialists’ Collaborative Group (EBCTCG)
has performed a meta-analysis on a large num-
ber of clinical trials, allowing for analysis of
small subsets including the elderly, and much
of the basis for systemic therapy in the elderly
comes from this data.
For hormone-receptor-positive tumors, selec-
tive estrogen receptor modulators (SERMs) and
aromatase inhibitors (AIs) clearly reduce recur-
rence and mortality and are well tolerated in
the elderly population. Unless the patient has
an extremely good-prognosis tumor or signifi-
cant comorbidity that precludes it, hormonal
therapy should be strongly considered. Tamox-
ifen can reduce breast cancer mortality by 31%
in postmenopausal women, regardless of age,
and the side effects (vasomotor symptoms,
endometrial cancer, thromboembolic disease)
are infrequent and do not significantly contrib-
ute to the likelihood of dying of nonbreast can-
cer
causes.
AIs
are
slightly
better
than
tamoxifen, improving disease free survival by
3% to 5%. This effect was most pronounced in
women over 64 years of age. For women who
took 5 years of tamoxifen, the addition of letro-
zole improved overall survival in patients who
were node positive. For women who took 2 to
3 years of tamoxifen, switching to an AI, as
opposed to staying on tamoxifen for the full 5
years, improved disease-free survival. Therefore
postmenopausal women should have an AI as
part of their hormonal therapy, although which
agent and when to introduce it is less clear. The
major complication of the AIs is musculoskele-
tal complications, including osteoporotic frac-
tures. These women should undergo baseline
and yearly bone densitometry.
Adjuvant chemotherapy decisions are more
difficult because there is a smaller benefit and
more side effects to consider. This includes the
addition of chemotherapy to hormonal therapy
in patients who are hormone-receptor positive
and the systemic options for patients who are
hormone-receptor negative. Even if a benefit is
present, the side effects of chemotherapy can
be more significant in older women. Myelosup-
pression and neutropenic infections increase
with age. Age is a known risk factor for anthracy-
cline-associated cardiac toxicity, and age is asso-
ciated with higher rates of cardiomyopathy in
women
treated
with
chemotherapy.
An
increased mortality rate secondary to chemo-
therapy has been reported in older women,
which may offset some of the benefit. It is hard
to truly study this, even prospectively, because
of the selection bias in entering older women
onto clinical trials (as a result of both strict entry
criteria and physician bias). The EBCTCG
overview is limited by the small number of
women over 70 in the clinical trials and the lack
of data regarding newer agents. However, it
seems unlikely
that
elderly
women
with
node-negative
disease
would
benefit
from
331
22—BREAST CANCER IN SPECIAL POPULATIONS

adjuvant chemotherapy. Several randomized
trials, including National Surgical and Adju-
vant Breast Project (NSABP) data, show a
decreasing impact of adjuvant chemotherapy
with age among node-negative patients. A
more significant impact of chemotherapy is
seen among patients who are node positive.
Trastuzumab may be a good choice in Her-2/
neu-positive tumors among elderly patients
with good baseline cardiac function, although
Her-2/neu overexpression decreases with age.
A more detailed discussion of systemic therapy
in the elderly population is beyond the scope
of this textbook; however, the complexity of
these decisions underscore the importance
of axillary staging among older patients and
argues against the routine avoidance of SLN
biopsy among women over a certain age. As
with so many situations in breast cancer, a mul-
tidisciplinary approach is mandated.
Breast Cancer among African
American Women
Although the treatment of breast cancer among
African American women is identical to that of
Anglo American women, there are several dif-
ferences in disease presentation and outcome
that are important to recognize. Breast cancer
incidence among African American women is
lower than that of Anglo American women.
Despite this, the mortality rates are paradoxi-
cally higher. This is partly explained by the
more advanced stage at which African Ameri-
can women tend to present; however, the rea-
sons for this are not completely clear.
It
might
be
immediately
assumed
that
the advanced stage at presentation, and the
increased mortality, can be attributed to socio-
economic factors and barriers to screening and
early diagnosis. Although this certainly plays a
part, there also appear to be some biologic dif-
ferences between breast cancer in the African
American population and their Anglo counter-
parts. Some evidence for this comes from the
association of age and breast cancer develop-
ment. Although breast cancer risk increases as
a function of age for both groups, African
American women have a higher incidence of
breast cancer under the age of 45 than do
Anglo women. These rates tend to equalize
around the fifth decade. Over the age of 50,
incidence rates for Anglo women surpasses
those of African American women, resulting
in a higher lifetime risk. Whereas 20% of
Anglo patients with breast cancer are younger
than 50 years of age, this number rises to
30% to 40% for African American patients
with breast cancer.
This may represent a difference in the biology
of the disease or may be related to a difference in
risk factors. As previously described, there is a
short-term increased risk of breast cancer in
the postpartum period with premenopausal
women. The higher prevalence of early child-
bearing among African American women may
increase the incidence below age 50 and ulti-
mately decrease the risk of breast cancer later in
life. Another potential explanation is in differ-
ences in diet and other environmental factors.
There may also be genetic factors at play.
Breast cancer among women in the Ghanaian
and Nigerian populations of western Africa
(who share a common ancestry with present
generation African American) have similarities
to that of African American women (younger
age of onset, higher rate of ER-negative dis-
ease). This suggests the possible contribution
of founder effects.
Breast
cancer
among
African
American
women is a more aggressive disease, with higher
rates of adverse prognostic factors such as hor-
mone-receptor negativity, stage at presentation,
and aneuploid tumors. This not only suggests a
more aggressive disease, but it also limits thera-
peutic options. African American cancers are
more likely to be node positive, even when cor-
recting for age and tumor size. This, in part, con-
tributes to the decreased survival, but does not
completely explain it. Among patients in the
Detroit SEER-based tumor registry, even after
adjusting for age, tumor size, nodal status, and
hormone-receptor status, there was a signifi-
cantly elevated mortality risk for young African
American women compared to Anglo American
women. This suggests that beyond more aggres-
sive disease, socioeconomic status may impact
treatment as well as screening. Poverty, lack of
insurance, restricted access to health care, and
possibly discriminatory practices within the
health care system may not only prevent Afri-
can American women from being diagnosed ear-
lier, but also limit treatment options. Does
socioeconomic status completely explain these
disparities? It does not appear so. A meta-analy-
sis of 14 studies looking at the difference in sur-
vival between African American and Anglo
American women showed that even when socio-
economic status is controlled for, race is still an
independent and significant predictor of mortal-
ity risk. Data from clinical trials alsosupports this
finding. Therefore, it appears that the more
aggressive disease and worse outcome seen
332
SURGICAL FOUNDATIONS: ESSENTIALS OF BREAST SURGERY

among African American women compared
with Anglo American women is the result of sev-
eral factors. These include inherent genetic dif-
ferences
between
the
two
populations,
differences in risk factors impacting the biology
of the disease, and disparities in screening and
delivery of treatment.
Breast Cancer among Other
Ethnicities
The Hispanic American community is the most
rapidly growing minority in the United States,
and breast cancer among Hispanic American
women has some similarities to the African
American population. As with African American
women, socioeconomic disadvantages also play
a significant role, with poverty and lack of insur-
ance providing barriers to screening and treat-
ment. Compared with non-Hispanic women,
Hispanic Americans appear to have a younger
age distribution and lower survival rate. There
is significantly less research in this area, and it
is difficult to fully evaluate the epidemiology of
breast cancer in Hispanic American women
because of the diversity within the population.
Hispanic Americans originate from Mexico,
Puerto Rico, Cuba, Central America, South
America, Spain, and Portugal, each with differ-
ent genetic, cultural, and dietary backgrounds.
Breast cancer among the Asian American pop-
ulation provides interesting data regarding the
causes of breast cancer. Historically, breast can-
cer incidence has been low among women
who originate or reside from an Asian country.
Studies of Asian women who moved to the
United States demonstrate a strong environ-
mental cause of breast cancer because the risk
of breast cancer increases with the length of
time spent in the United States and number of
generations who have lived here. Thus, an Asian
woman who moves to the United States has a
higher risk than a woman who lives in an Asian
country, and an Asian woman born in the
United States has an even higher risk, nearly
approximating that of a non-Asian woman born
in the United States. Similarly, breast cancer
rates in Asia have increased as countries have
adopted westernized cultural practices. These
data have prompted multiple searches for the
reproductive,
dietary
or
cultural
practices
thought to account for these trends, with lim-
ited success. Epidemiologic studies among Asian
Americans women is also hampered by the het-
erogeneity
of
the
population,
which
may
include women from Japan, China, Korea,
Hawaii, the Philippines, India, Pakistan, and
other countries, again all with different back-
grounds, diets, and cultures.
Suggested Readings
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23
Other Tumors of the Breast
PHYLLODES TUMORS
FIBROMATOSIS OF THE BREAST
SARCOMA
Angiosarcoma of the Breast
LYMPHOMA
METASTASES TO THE BREAST
Other Tumors of the Breast: Key Points
Know the difference in presentation between a phyllodes tumor
and a fibroadenoma.
Describe the surgical treatment of phyllodes tumor.
Describe the surgical treatment of fibromatosis of the breast.
Understand the risk factors for sarcoma, including those specific to breast
cancer therapy.
Describe the clinical presentation of angiosarcoma of the breast.
Know the multidisciplinary treatment of soft tissue sarcoma.
Be familiar with the clinical presentation and management of breast
lymphoma.
Phyllodes Tumors
Phyllodes tumors encompass an unusual spec-
trum of fibroepithelial tumors of the breast that
exhibit a range of clinical behavior. Overall they
represent less than 1% of all breast neoplasms.
Although the median age is 45, they have been
described
both
in
adolescents
and
elderly
patients. This is an older age distribution than
with fibroadenoma; so a fibroadenoma-like
mass in older patients should raise a concern
for
phyllodes.
Patients
with
Li-Fraumeni
syndrome have a higher risk of phyllodes
tumors. They have also been described in men
who have gynecomastia.
Phyllodes tumors most commonly present as
a palpable mass in the breast. Because they
often have a biphasic growth phase, patients
may seek medical attention for a mass that
has been stable for a long period of time but
recently started to enlarge. The lesions can get
quite large, with phyllodes tumors over 20 cm
having been reported, although even extremely
large tumors can still be benign histologically.
335

On examination, the masses are similar to
fibroadenomas; mobile, round, smooth, and
well-defined margins (Box 23–1). Even with
malignant phyllodes tumors, signs associated
with malignancy such as skin or nipple retrac-
tion or bloody nipple discharge are rare. Lymph
node involvement is also quite rare, although
some patients may have palpable adenopathy.
The workup is similar to any new or enlarging
breast mass, including mammogram, ultrasound,
and biopsy. The biggest difficulty is differentiat-
ing these tumors from fibroadenoma. Not only
do they feel like fibroadenomas, but on imaging
they also have radiographic findings that mimic
fibroadenomas (oval or round, solid, hypoechoic,
well-circumscribed masses). On ultrasound, there
may be coarse microcalcifications present or a
cystic area within the solid mass.
Histologically, phyllodes tumors are character-
ized by both epithelial and stromal elements. Itis
the stroma, however, that is truly distinguish-
ing. Clonal analysis reveals that the epithelial
component is polyclonal, whereas the stromal
component is monoclonal, demonstrating that
the stroma is the neoplastic component of the
tumor. Under the microscope these tumors con-
tain elongated ductal elements and papillary
protrusions of connective tissue lined by epithe-
lium that produce the classic leaflike appearan-
ce (Fig. 23–1). The stromal overgrowth and
hypercellularity distinguish these lesions from
fibroadenomas.
Unfortunately, fine-needle aspiration (FNA)
carries a high rate of false-negative results for diag-
nosing phyllodes tumors because they have a
heterogeneous composition. Core-needle biopsy
is much more accurate, although still may be
hampered by sampling error. This presents a clin-
ical problem because many of these patients will
present with what appears to be a fibroadenoma,
for which FNA (combined with clinical and radi-
ologic evaluation and an experienced cytopathol-
ogist) is a useful tool. Clinicians should lean
towardcore-needle biopsy if they suspect a higher
likelihood of a phyllodes tumor. This would
include any long-standing mass that suddenly
gets larger, a mass greater than 3 cm in size or a
fibroadenoma-like mass in a patient over the age
of 35. Also any radiographic findings not consis-
tent with fibroadenoma, such as cystic areas
within a solid mass, should prompt a core-needle
biopsy. If an FNA was performed and there were
either hypercellular stromal fragments or other
indeterminate findings, either a core or excisional
biopsy should be performed.
Phyllodes tumors are characterized as benign,
borderline, or malignant based on their histo-
logic
appearance.
Increased
cellular
atypia,
mitotic activity, stromal overgrowth, and tumor
necrosis are associated with malignant potential.
One of the most important features is the tumor
margin; whether it is circumscribed or infiltra-
tive. Over half of phyllodes tumors are benign,
whereas
about
one
quarter
are
malignant.
Surprisingly, there is slightly less correlation with
outcome and histologic features. Benign tumors
can recur and even spread and malignant lesions
can have indolent courses. Because of this,
some
authors
have
suggested
approaching
all phyllodes tumors as though they have
BOX 23–1 FEATURES SUSPICIOUS
FOR PHYLLODES TUMOR VERSUS
FIBROADENOMA


Rapid growth


Greater than 3 cm


Sudden increase in growth of a long-
standing breast mass


Fibroadenoma-like mass in patient old
than 35 years of age


Rounded borders or lobulated
appearance on mammogram


Cystic area within solid mass on
ultrasound


Hypercellular stromal fragments on fine-
needle aspiration


Indeterminate features on fine-needle
aspiration or core-needle biopsy
Figure 23–1. Histology of phyllodes tumor. Phyl-
lodes tumors are differentiated from fibroadenomas
by the expanded and increased cellularity of the stro-
mal component. The distinction between benign,
borderline, and malignant is based on stromal cellu-
larity, cytologic atypia, mitoses, and necrosis. (Image
courtesy of Dr. Maria Braman, Department of Pathol-
ogy, University of Michigan).
336
SURGICAL FOUNDATIONS: ESSENTIALS OF BREAST SURGERY

some malignant potential. It is important to
keep in mind that overall, phyllodes tumors
have a favorable prognosis.
Once a diagnosis of phyllodes tumor is made,
surgical excision is indicated. The standard rec-
ommendation is a wide excision with 1-cm mar-
gins. The 1-cm margin is recommended because
there may be microscopic projections of tumor
extending into the pseudocapsule of compressed
breast tissue that surround these lesions. Often
these are simply enucleated because they are sus-
pected to be fibroadenomas. This is clearly inad-
equate and reexcision is recommended. The data
is less clear when a phyllodes tumor is diagnosed
after a negative, but narrow, margin excision. For
borderline or malignant tumors, reexcision is
clearly indicated. For clearly benign phyllodes
tumors, this is less clear. However, given the dif-
ficulties in pathologic classification and the
potential of even benign lesions to recur, a reex-
cision is reasonable. In cases where tumor size
precludes breast conservation, simple mastec-
tomy is indicated. Sentinel lymph node (SLN)
biopsy or routine axillary dissection is not indi-
cated because lymph node metastases occur in
less than 5% of patients. Axillary lymph node
dissection (ALND) should be performed in
patients with confirmed pathologic nodes.
The role of adjuvant radiation therapy is con-
troversial. There is no prospective randomized
data to base decisions on. It does not appear indi-
cated when a 1-cm margin has been obtained
and unlikely to be of benefit when a clearly
benign phyllodes tumor has been excised with
negative margins. It should be considered in
situations in which negative margins cannot be
obtained. The role of adjuvant chemotherapy is
clearer—there is no role. Hormone-receptor
expression on the stromal component is rare
and so there is no role for measuring these or
treating
with
hormonal
therapy.
Although
malignant phyllodes tumors have a risk of dis-
tant recurrence, chemotherapy has limited effi-
cacy and so probably provides little benefit in
the adjuvant setting.
The most common type of recurrence is local,
occurring in approximately 15% of patients.
Most local recurrences are within 2 years, are
usually the same histology (although transfor-
mation to more aggressive subtypes has been
reported), and in most cases, are not associated
with distant recurrence. Treatment should be
reexcision with 1-cm margins if possible. Some
authors have argued for radiation after reexci-
sion of a recurrent phyllodes because patients
with one local recurrence have a higher risk of
further episodes of recurrence. However, this is
a controversial recommendation. If a reexcision
with 1-cm margins is not possible, mastectomy
is indicated.
Overall, approximately 5% to 10% of patients
with phyllodes tumors will develop distant dis-
ease. This is higher for malignant phyllodes
tumors, closer to 20%. The metastases are com-
posed of only the stromal elements, with no epi-
thelial component. Average survival of patients
with metastatic phyllodes tumors is less than
2 years. Chemotherapy is indicated, although
multiple single and combination regimens have
been used with varying success and responses
are generally of short duration. The National
Comprehensive Cancer Network (NCCN) re-
commends that the treatment of metastatic
phyllodes tumors follow the guidelines for meta-
static soft tissue sarcoma.
Fibromatosis of the Breast
Fibromatosis of the breast is similar to fibromato-
sis in other sites, such as desmoid tumors of the
abdominal wall. Although they do not metasta-
size, these lesions have a high propensity for
local recurrence and possibly local invasion.
Fibromatosis is characterized by a nonencapsu-
lated proliferation of spindle cells. Fibromatosis
of the breast will often present like invasive
cancer with a palpable mass that may have asso-
ciated skin retraction or chest wall fixation.
Imaging will also appear consistent with in-
vasive breast cancer. However, on pathology,
these lesions demonstrate interlacing bundles
of spindle-shaped cells surrounded by collagen,
with minimal if any cytologic atypia. The prolif-
eration surrounds the ducts and lobules without
destroying them.
The treatment of fibromatosis is wide exci-
sion with careful assessment of the margins
to assure complete resection. Otherwise local
recurrence is highly likely. Radiation therapy
may be considered if complete excision is not
possible, but the goal should be widely nega-
tive margins whenever possible. Low levels of
estrogen receptor (ER) and progesterone recep-
tor (PR) expression have been described, as has
response to tamoxifen, and so this should be
considered when excision is not possible.
Sarcoma
Sarcomas are malignant tumors of mesenchy-
mal tissue. They can occur anywhere in the
body, including in the breast, although this is
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23—OTHER TUMORS OF THE BREAST

quite rare, accounting for less than 1% of breast
malignancies. There are several risk factors that
have been identified for sarcoma. Genetic con-
ditions may predispose to sarcoma including
Li-Fraumeni syndrome, Gardner syndrome, or
neurofibromatosis type 1. There are also envi-
ronmental exposures that have been linked to
sarcoma. Vinyl chloride, arsenic compounds,
and herbicides are some of the agents that have
been implicated. Several viruses have also been
associated with sarcoma such as the human
immunodeficiency virus (HIV).
There are two risk factors for sarcoma that are
particularly worrisome for the development of
breast sarcoma. The first of these is ionizing radi-
ation. The risk of postirradiation sarcoma in-
creases with the dose of radiation used (it is
rarely seen with doses less than 40 Gy). The aver-
age latency period for sarcomas after radiation is
approximately 5 to 12 years (shorter for angio-
sarcomas than other histologies). Fortunately,
the risk of secondary sarcoma in women who
undergo radiation for breast-conserving therapy
(BCT) is quite small. The cumulative incidences
of radiation induced sarcoma are approximately
0.2% at 10 years and 0.78% at 30 years.
Another risk factor for sarcoma is chronic
edema, which can of course be a complication
of breast therapy. Angiosarcomas of the arm or
breast in women with chronic lymphedema
after breast cancer treatment is known as Stew-
art-Treves syndrome.
Breast sarcomas usually present as a large,
painless, firm mass within the breast, a presen-
tation similar to fibroadenomas or adenocarci-
noma. They rarely have any overlying skin or
nipple changes. Angiosarcomas of the breast
may have some color changes in the overlying
skin, either a bluish tint or erythema. Sarco-
mas often grow faster than epithelial breast
cancer and so may be larger in size when diag-
nosed. On mammography, calcifications, spi-
culations, and other signs associated with
breast cancer are rarely present. Thus, these
lesions may be mistaken for benign tumors.
The diagnosis will come down to the biopsy.
Common subtypes within the breast include
fibrosarcoma, angiosarcoma, malignant fibrous
histiocytoma (MFH), myxofibrosarcoma, and lei-
omyosarcoma. Outside of angiosarcoma, which
has a much worse prognosis, the histologic sub-
type is not a significant prognostic factor. Core-
needle biopsy is often adequate, but sometimes
sarcomas have necrotic centers and the core-
needle biopsy will not retrieve enough viable
tissue to make a diagnosis. In this case an exci-
sional or incisional biopsy may be indicated. This
may also be needed to differentiate a primary
breast sarcoma from a metaplastic carcinoma.
The latter is diagnosed because of associated inva-
sive carcinoma or in situ disease.
Once the diagnosis is made, staging should
include a computed tomography (CT) scan of
the chest to rule out lung metastases (the most
common site of spread from sarcoma) and serve
as a baseline for future follow-up. A magnetic
resonance imaging (MRI) of the breast may also
be useful in planning surgical therapy. As is
often recommended with breast cancer, patients
diagnosed with sarcoma should be referred to a
multidisciplinary sarcoma center. Because sar-
coma is a rarer disease than breast cancer, there
are less institutions with experience treating
sarcoma, and experience is critically important
given the complexities of sarcoma management.
The use of radiation therapy and chemotherapy
is more controversial for sarcoma, as is the use
of preoperative versus postoperative therapy.
The most important component of sarcoma
therapy is surgery, and this will primarily consist
ofmastectomy, although wide local excision with
negative margins may be acceptable for some
patients (small, low-grade tumors). When appro-
priate, wide local excision has been shown to
have equal outcomes to mastectomy, as along as
negative
surgical
margins
are
obtained.
As
sarcomas rarely spread to the regional nodes,
SLN biopsy or ALND is not routinely recom-
mended. Some histologic subtypes do have
higher incidences of regional spread and may jus-
tify SLN biopsy. These include breast liposarco-
mas,
carcinosarcomas,
synovial
sarcomas,
epithelioid sarcomas, and possibly rhabdomyo-
sarcomas (although these subtypes are quite rare
within the breast). In some cases, a simple mas-
tectomy may not be adequate because skin or
muscle involvement may require a more radical
excision. The benefit of radiation is controversial
for breast sarcoma, but given the benefit for
extremity soft tissue sarcoma, is generally recom-
mended for patients with high-grade tumors,
tumors greater than 2 cm or for those in whom
positive margins can not be obtained. Chemo-
therapy is more controversial. A thorough review
of the pathology and a treatment plan devised by
a tumor board consisting of medical, radiation,
and surgical oncologists with experience in
sarcoma is paramount to successful treatment.
Angiosarcoma of the Breast
Sarcomas are extremely heterogeneous, but
angiosarcomas
deserve
special
mention
because they may be associated with therapies
338
SURGICAL FOUNDATIONS: ESSENTIALS OF BREAST SURGERY

that are specific to breast cancer; they are the
most common type of breast sarcoma in many
series; and they may present differently than
other types of sarcoma. Angiosarcomas of the
breast are categorized as primary or secondary,
with secondary angiosarcomas occurring in
the face of breast lymphedema or radiation
therapy. Although primary angiosarcomas typ-
ically occur in the second to fourth decade of
life,
secondary
angiosarcomas
occur
after
breast cancer treatment and thus are usually
diagnosed in women over 50.
As with other sarcomas, angiosarcomas may
often present as a superficial, palpable, painless
mass. However, there may be a blue or purple
discoloration and more than one mass. Some
patients may present with complaints of ecchy-
mosis, but there is no history of trauma. Diffuse
breast enlargement may be present. Any woman
who underwent breast or chest wall radiation
and now presents with a new mass or discolor-
ation in the irradiated field must prompt suspi-
cion and biopsy. Angiosarcomas may often
extend well beyond what is apparent clinically.
Wide excision is rarely adequate, and most
patients will require a mastectomy or a more
radical resection including a wider area of skin
or concomitant chest wall resection. Once diag-
nosed, MRI should be obtained to help delineate
the extent of the tumor, although MRI can
underestimate this as well. Radiation therapy is
recommended as an adjunct to surgery, but
many of these patients have already had radia-
tion. It is important to review the dose and fields
of the previous radiation. Chemotherapy is con-
troversial, but given the extremely poor progno-
sis, often recommended. These are aggressive
tumors with an extremely poor outcome. They
metastasize early to the lung, liver, and also to
the contralateral breast, bones, and skin. The
median survival from the time of diagnosis is
about 15 months. Future therapies may include
vascular-targeting therapies such as antiangio-
genesis agents or tyrosine kinase inhibitors. As
with all sarcomas, timely referral to a center spe-
cializing in sarcoma is strongly recommended.
Lymphoma
Lymphoma of the breast is quite rare, making up
less than 0.5% of breast malignancies. Breast
lymphomas can either be primary or secondary.
Secondary breast lymphoma is more readily
recognized because the patients have evidence
of concurrent widespread disease. Patients with
primary breast lymphoma have no evidence of
widespread disease beyond the breast, although
axillary lymph nodes or bone marrow may be
involved. The clinical and radiologic presenta-
tion of primary breast lymphoma is non-
specific, and there is little to suggest lymphoma
as compared with other breast malignancies.
Most present as a painless mass in the breast,
although there may be some thickening of the
skin or pain, and they tend to be more rapidly
growing than typical breast cancers. Enlarged
axillary lymph nodes may also be present. The
classic “B” symptoms of lymphoma (fever,
weight loss, night sweats) are only rarely pres-
ent. Mammography and ultrasound are non-
specific. Thus the diagnosis comes down to the
biopsy, which will also require flow cytometry.
Therefore an FNA or core-needle biopsy might
suggest the diagnosis, but an excisional (or inci-
sional) biopsy is usually needed to obtain ade-
quate tissue for staining and flow cytometry.
Most breast lymphomas are of B-cell origin.
Primary breast lymphomas tend to be large cell
tumors, whereas secondary breast lymphomas
are more commonly diffuse small cell tumors.
Hodgkin lymphoma and T-cell lymphomas of
the breast have been described.
Once diagnosed, the next step should be CT
staging of the neck, chest, abdomen, and pelvis
and bone marrow biopsy. If the disease is wide-
spread or felt to be secondary lymphoma, sys-
temic therapy is initiated. For cases of primary
breast lymphoma, the treatment is guided by
the grade and subtype of the disease. Low-grade
tumors may be treated by local excision alone,
or with radiation therapy. High-grade tumors
should also be treated with chemotherapy.
There is no indication for radical surgery, such
as mastectomy or ALND because the prognosis
is similar to lymphomas at other sites and
mostly dependent on systemic therapy. These
patients are best seen and evaluated at a multi-
disciplinary lymphoma clinic.
Metastases to the Breast
The breast is an unusual place for other cancers
to metastasize to. The most common primary
tumors that have been described to spread to
breast tissue include lymphomas, lung cancer,
melanoma, renal cell carcinoma, and ovarian
cancer. Other types that have been described
include prostate, thyroid, rectal, gastroesopha-
geal, cervical, vaginal, or pancreatic cancer.
Although many patients will have a history of a
previous cancer, some will present synchro-
nously and the breast metastasis may be the first
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23—OTHER TUMORS OF THE BREAST