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146
9
Mark Schaverien
Cameron Raine
Breast reconstruction
Introduction
Surgery for breast cancer is not finished until the
reconstruction has been completed in those patients
who choose to have it. Mastectomy for breast can-
cer can lead to negative psychological effects on the
patient and breast reconstruction, whether immedi-
ate or delayed, can provide significant psychosocial
benefits.1–4 Even the most sophisticated breast re-
construction, however, will never fully replicate the
breast that has been lost in terms of feel, movement,
and erogenous sensation, although some spontane-
ous sensory recovery may occur.5
Women must be fully informed of all available op-
tions for breast reconstruction at the time of planning
initial surgical treatment so that they can make in-
formed decisions, even if it is their personal preference
to have a delayed reconstruction or no reconstruction
at all.6,7 The ultimate goal of breast reconstruction is
to produce a ‘breast’ that satisfies the patient's wishes
and matches the contralateral breast, also improving
the preoperative breast aesthetics if possible. Breast
reconstruction may be either autologous, non-autol-
ogous, or a combination of the two, with the use of
symmetrising mastopexy, reduction or augmentation
surgery if necessary.8 The decision regarding the tim-
ing and technique of breast reconstruction should be
made by the patient and a multidisciplinary breast
cancer team, which should include reconstructive sur-
geons who are able to provide the full range of com-
monly used reconstructive procedures.
Timing
The principal aim of breast cancer surgery is to
provide safe and successful oncological treatment.
The decision for delayed or immediate breast recon-
struction and the reconstruction offered may be af-
fected by the anticipated need for adjuvant therapy.8
Immediate breast reconstruction
The main advantage of immediate breast reconstruc-
tion is that the patient does not have to spend any
time without a breast mound. It allows preservation
of the native breast skin envelope and inframammary
fold and therefore the reconstruction usually assumes
a more natural shape when the breast volume is re-
stored. The mastectomy skin flaps are pliable and un-
affected by soft-tissue contracture and scar, and have
not suffered the effects of radiotherapy. Skin-sparing
and subcutaneous mastectomy techniques can lead to
better cosmetic results, with a reduced need for con-
tralateral symmetrisation surgery.8–10
The disadvantages of immediate reconstruction are
the limited time for decision-making by the patient
due to the need to perform the oncological surgery,
increased operating time, and the difficulties of co­
ordinating two surgical teams where different surgeons
are required to perform the mastectomy and desired
reconstruction. Immediate breast ­reconstruction
does not compromise ­adjuvant ­treatment, although

Breast reconstruction
147
there is a potential in ­individual patients for com-
plications to result in a delay in starting adjuvant
treatment.8,11,12
The current indications for post-mastectomy
radiotherapy lead many patients to receive radio-
therapy as part of their breast reconstruction al-
gorithm. The possibility of radiotherapy should
be anticipated before proceeding with immediate
breast reconstruction. Radiotherapy can have det-
rimental effects on breast reconstructions, but these
can be reduced by choosing autologous reconstruc-
tion over implant-based procedures. With current
radiotherapy delivery regimens good cosmetic out-
comes can be expected in the majority of cases.13,14
Delayed-immediate reconstruction is also an option
in these circumstances. Whether the use of acellu-
lar dermal matrix confers any protective effect for
implant reconstruction requiring radiotherapy is
unclear at present.15
It is now well established that immediate breast
reconstruction does not adversely affect breast can-
cer outcome.13,16–18 Breast reconstruction may be
indicated even in advanced disease to control lo-
coregional disease and improve quality of remain-
ing life.8,19,20 There is also evidence to suggest that
survival may be improved by removal of the pri-
mary tumour.21
Where the viability of parts of the mastectomy skin
flap is uncertain, it may be necessary to delay im-
plant reconstruction to avoid risk of exposure of the
prosthesis. In the case of autologous reconstruction
it may be prudent not to de-epithelialise the part of
the flap skin paddle under the questionable part of
the mastectomy skin flap until any area of necrosis
has declared itself over the subsequent few days.
Delayed breast reconstruction
Delayed breast reconstruction allows the patient
time for decision-making, psychological adjustment
following their breast cancer diagnosis and mastec-
tomy, and allows the full pathology to be available
prior to reconstructive surgery. It avoids any po-
tential delay of adjuvant treatment and also avoids
any detrimental effects of adjuvant therapy on the
reconstruction. In addition, the mastectomy skin
flaps can be allowed to heal if necessary and any
skin damaged by radiotherapy can be excised. The
main disadvantage is that skin-sparing ­mastectomy
techniques cannot be used due to the poor aes-
thetic outcomes of a contracted skin envelope, and
therefore a much larger skin paddle is required. In
addition, a second operation and episode of hos-
pitalisation is required and treatment costs are in-
creased compared with immediate reconstruction
(see Box 9.1).22
Advantages of immediate breast
reconstruction
• Potential for a single operation and one period of
hospitalisation
• Maximum preservation of breast skin
• Preservation of the inframammary fold
• Good-quality skin flaps
• Better cosmetic results for skin-sparing mastectomy
• Reduced need for balancing surgery to the contralateral
breast
• Lower costs than delayed reconstruction
Disadvantages of immediate
reconstruction
• Limited time for decision-making by patient
• Increased single operating time
• Difficulties of coordinating two surgical teams when
required
• Potential in individual patients for complications to
result in delay of adjuvant treatment
Advantages of delayed breast
reconstruction
• Allows unlimited time for decision-making by the
patient
• Avoids any potential delay of adjuvant treatment
• Avoids detrimental effects of radiotherapy or
chemotherapy on the reconstruction
Disadvantages of delayed breast
reconstruction
• Requires replacement of a larger amount of
breast skin
• Mastectomy flaps may be thin, scarred, contracted
or irradiated
• Mastectomy scar may be poorly positioned
• May result in a less aesthetically pleasing outcome
• Requires separate episode of hospitalisation
• Increased treatment cost compared with immediate
breast reconstruction
Box 9.1  •  Advantages and disadvantages of immediate
and delayed breast reconstruction

Chapter 9
148
Delayed-immediate breast
reconstruction
Delayed-immediate breast reconstruction provides
some of the benefits of both immediate and delayed
breast reconstruction. A skin-sparing mastectomy
and immediate reconstruction with a tissue ex-
pander is performed. Once the final pathology is
available, patients who do not require adjuvant ra-
diotherapy proceed to immediate breast reconstruc-
tion. Those who require radiotherapy have their
expander fully deflated prior to radiotherapy to al-
low optimal delivery of the radiotherapy, following
which the expander is serially re-expanded within a
few weeks of completion of radiotherapy to prevent
contraction of the skin envelope whilst awaiting de-
layed reconstruction.23
Contraindications
Contraindications to breast reconstruction include
serious comorbidities, unresectable local chest wall
disease, or rapidly progressive uncontrollable meta-
static disease.
Techniques
Breast reconstruction involves the replacement of
breast volume and may involve the replacement of
breast skin and nipple–areola complex. Surgical op-
tions for reconstruction include the use of breast im-
plants, tissue expanders or expander implants, and
the use of autologous tissue with or without an im-
plant. The most commonly used surgical techniques
are tissue expansion, latissimus dorsi musculocuta-
neous flap with or without implant, or the use of a
free lower abdominal tissue flap.
Implant-based techniques have the shortest operat-
ing time, inpatient stay and fastest recovery, but these
initial advantages are offset by the finite lifespan of
the prosthesis, requiring exchange in the future, and
the deterioration of aesthetic appearance with time.
The reconstructed breast will not behave similarly
to a normal breast and the larger or more ptotic the
contralateral breast is, the harder it will be to ob-
tain symmetry unless the contralateral breast is aug-
mented. This option may suit women who are simply
seeking symmetry in a bra and do not wish to use an
external prosthesis.
The aesthetics of autologous reconstruction do
not deteriorate with time as with implant-based re-
construction, and are considered to be superior in
terms of more natural appearance, feel and dura-
bility.24 Autologous tissue can also better withstand
radiotherapy.25,26
Non-autologous reconstruction
Breast reconstruction by tissue expansion involves
the serial expansion of chest-wall tissue to replace
permanently the skin lost following mastectomy by
repeated injections of saline into an inflatable sili-
cone expander placed behind the pectoralis major
muscle28 (Fig. 9.1). This may either be followed by
replacement with a definitive implant once expan-
sion is complete, or in the case of a permanent ex-
pandable breast implant that consists of a silicone
outer lumen and an expandable saline inner lumen,
only the filling port may need removal if it is not
integrated into the device.
The outcomes of the technique are dependent on
careful patient and implant selection. The technique
appears simple and is generally good for restoring
volume (Fig. 9.2), but it is difficult to create ptosis,
and therefore good symmetry with the unaffected
breast and true symmetry with implant-based re-
construction is best achieved by bilateral procedures
(Fig. 9.3).
Indications
This technique is most suitable for patients with
small non-ptotic breasts, when performing bilateral
reconstruction, or for women who are happy to ac-
cept a mastopexy or augmentation procedure on the
opposite breast. It is ideal for patients who want
minimal scarring and are unwilling or unfit to un-
dergo autologous tissue reconstruction.8,27
The timing and type of reconstruction need
to be individualised to the need for adjuvant
treatment, risk factors for surgery, breast size, body
habitus, skin quality and thickness, availability and
quality of flap donor sites, the patient's general
health and smoking habits, and the contralateral
breast. Patients must be fully informed on the
reconstructive options available so that they can
make high-quality decisions regarding their care,
and the reconstructive surgical team must be
able to provide the full range of commonly used
reconstructive options.8,27

Breast reconstruction
149
Contraindications
Patients are unsuitable for implant reconstruction
if the chest-wall tissues are very thin, if the mastec-
tomy skins flaps are of uncertain viability, or if the
pectoralis major muscle is absent, either ­congenitally
or following radical mastectomy. Radiotherapy sig-
nificantly increases the risk of complications and
diminishes the aesthetic result of implant/expander
breast reconstruction.25,26 This may therefore not be
the best method of reconstruction if adjuvant radio-
therapy is planned or has already been given.
Surgical techniques
The inframammary fold is an important landmark
for implant reconstruction that can be preserved
safely during mastectomy and should be restored
with sutures if it has been violated. Careful choice
of the expander is important, and the size should
take into account the base width, height and projec-
tion of the normal, intact breast.29
Tissue expanders are placed under the pectoralis
major muscle and the inferolateral portion may be
covered by serratus fascia, allo- or xenograft, or the
serratus anterior and external oblique muscles in a
submuscular plane to reduce palpability. There is
growing popularity for using acellular dermal ma-
trix, most commonly human (AlloDerm®) or porcine
(Strattice®) skin derived, as well as bovine skin and
pericardium, to cover the inferolateral portion of the
implant (Fig. 9.4). This potentially allows a one-stage
immediate implant reconstruction or shortens the
time taken for expansion. This technique expands
the indications for immediate implant-based recon-
struction in women with large ptotic breasts; how-
ever, these advantages need to be offset against the
costs of the product. In the setting of one- versus two-
stage reconstruction, though, the initial increased
costs may be offset overall. Acellular dermal ma-
trices (ADM) do allow much better ­inframammary
Figure 9.2  •  Delayed breast reconstruction by tissue
expansion. Courtesy of Eva M. Weiler-Mithoff.
Figure 9.3  •  Bilateral mastectomy with breast
reconstruction with implants and nipple reconstructions.
Figure 9.1  •  Breast reconstruction with submuscular
tissue expander. Courtesy of Eva M. Weiler-Mithoff.

Chapter 9
150
fold ­definition. They are not without complications.
There is a higher rate of seroma, infection and recon-
struction failure with the use of ADMs. The key is to
try and place the mastectomy incision over muscle
and not over the matrix when inserted and to ensure
primary wound healing by refreshing the mastectomy
wound. This is achieved by excising the trauma-
tised skin edges at the end of the operation. A good
alternative in immediate reconstruction of large
ptotic breasts is to perform a skin-reducing mastec-
tomy and use the deepithelialised lower skin flap
sutured to the caudal edge of the pectoralis major
muscle to cover the inferolateral portion of the pros-
thesis as a vascularised dermal flap, although a con-
tralateral reduction procedure is usually necessary.
Tissue expansion can be used for immediate or de-
layed breast reconstruction (Fig. 9.5). The expander
is only partially inflated at insertion to allow clo-
sure of overlying mastectomy skin flaps without
tension. The actual expansion starts 2–4  weeks
­postoperatively following an interval for healing and
is usually performed at weekly intervals. The volume
of expansion at each occasion should be guided by
patient comfort. Overexpansion was a technique
that was used to create a degree of ptosis to pro-
duce a more natural-looking breast, but this is un-
necessary when anatomical devices are used. Once
expansion is completed, the expander is left in place
for 1–3 months to allow the skin envelope to main-
tain its stretch permanently. The expander is then
removed, a capsulectomy or capsulotomy is per-
formed, and a definitive implant is inserted based on
the width and height of the pocket and the desired
projection. Reconstruction of the breast mound can
therefore take up to 6 months using tissue expan-
sion. A slightly larger definitive prosthesis is often
used following expansion with an anatomical device
to reduce the risk of rotation, which can be problem-
atic. Revisional procedures are often required to op-
timise the aesthetic appearance of the reconstructed
breast, and over one-third of patients require further
surgery within the first 5 years after implant-based
breast reconstruction.30 In addition mastopexy, re-
duction or augmentation of the contralateral breast
and lipofilling are often required to improve symme-
try. The long-term aesthetic results of implant-based
reconstruction can be expected to decline with time,
independent of the implant type or volume, due to
gradual ptosis of the contralateral side and failure of
the implanted side to undergo normal ptosis, lead-
ing to late asymmetry.31 This procedure requires ap-
proximately 1 hour of operating time, a short period
of hospitalisation and 2–4 weeks of recovery time.
Complications
Early complications include haematoma, infection,
mastectomy skin flap necrosis and wound dehiscence,
and late complications include implant rupture/de-
flation, capsular contracture, implant malposition/
rotation, implant rippling, extrusion and asymmetry.
Even with the latest prosthetic materials and modern
radiation delivery techniques, the complication rate
for implant-based breast reconstruction in patients
undergoing post-­mastectomy radiation therapy may
be as high as 40%, and the extrusion rate is 15%.32
The commonest and least predictable complication
of implant reconstruction is capsular contracture,
which may lead to firmness and visible distortion
of the breast, as well as pain in advanced cases, and
may warrant surgical revision. The risk of capsular
Figure 9.4  •  One-stage reconstruction after mastectomy
with Strattice sling visible covering lower half of implant.
Figure 9.5  •  Right delayed reconstruction with implant
and Strattice. Left prophylactic mastectomy with
immediate reconstruction with implant and Strattice.

Breast reconstruction
151
contracture is significantly increased following radio-
therapy.33 There is some evidence that textured im-
plants may reduce the risk of capsular contracture.34
Lipofilling appears to ­improve capsular contracture
and can help ­improve cosmetic outcomes. It is par-
ticularly valuable for implant rippling and achieving
a greater degree of symmetry.
Autologous breast reconstruction
Background
Autologous breast reconstruction allows creation of
a breast whose texture and appearance match more
closely that which has been lost compared with an im-
plant-based reconstruction. In addition, the ­aesthetic
result of autologous breast reconstruction tends to
improve with time. While the latissimus dorsi (LD)
and transverse rectus abdominis ­musculocutaneous
(TRAM) flaps remain popular options for breast
reconstruction, there is increasing popularity of the
deep inferior epigastric artery (DIEP) flap due to its
reduced abdominal donor-site morbidity.
Autologous reconstruction is indicated for immedi-
ate breast reconstruction when adjuvant radiotherapy
is planned, in delayed breast reconstruction following
adjuvant radiotherapy, in patients with large ptotic
breasts, and in patients where previous implant re-
construction has failed. Abdominal flap reconstruc-
tion is ideal for those patients in whom an aesthetic
abdominoplasty may be seen as an advantage.
Latissimus dorsi (LD) flap reconstruction
The LD flap may be used either as a muscle or mus-
culocutaneous flap. With its excellent blood supply
to the overlying skin it affords a variety of skin pad-
dle designs that can be hidden within the bra strap
lines (Fig. 9.7). It is usually combined with an implant
and reduces clinically evident capsular contracture
and rippling of the prosthesis (Fig. 9.8). The extended
LD flap includes the subcutaneous fat overlying the
muscle deep to the superficial fascia to increase vol-
ume and reduce the chance of needing an implant
(Fig.  9.9). Where volume is still deficient with this
method, later lipofilling can be used to provide the
necessary volume without the need for an implant.
The pedicled LD flap has the lowest flap failure
rate of the autologous reconstructions available
and may be indicated in patients who are higher
risk for autologous reconstruction. The best indi-
cation is in cases where the abdomen is unsuitable
as a donor site either due to insufficient tissue vol-
ume or the presence of multiple scars, or where the
deep inferior epigastric pedicle has been previously
ligated. Disadvantages include a scar on the back,
possible shoulder stiffness and impairment of up-
per limb function. The functional deficit of the up-
per limb has been investigated in multiple studies,
and ­although its absence is well compensated for
by the teres major muscle, it is necessary to counsel
patients who have high demands of their upper
limb, in particular for activities involving shoul-
der extension and adduction such as climbing and
swimming, that this option may result in some
­functional ­deficit. Additional physiotherapy may
also be required to restore full shoulder mobility.35
Implant-based breast reconstruction is a
suitable option for those unwilling or unfit to undergo
autologous reconstruction. Patients do, however,
need to be counselled that the results tend to
deteriorate with time due to gradual ptosis of the
contralateral side and failure of the implant side to
undergo normal ptosis, leading to late asymmetry
despite contralateral symmetrising surgery31
(Fig. 9.6). In addition an implant has a finite lifespan
and may need replacement due to implant leakage
or rupture or due to capsular contracture.
Percentage
96.4%
86%
TRAM flap breast
reconstruction
Breast implant
reconstruction
0
25
50
75
100
0
12
24
36
48
60
72
84
96
Months
54%
94.2%
Figure 9.6  •  The actuarial percentage cosmetic outcome
for acceptable results for breast implant reconstruction
(lower line) and TRAM flap breast reconstruction with
estimates at 2 and 5 years. Adapted from Clough KB,
O'Donoghue JM, Fitoussi AD et al. Prospective evaluation
of late cosmetic results following breast reconstruction:
implant reconstruction. Plast Reconstr Surg 2001;
107:1702–9, and Clough BC, O'Donoghue JM, Fitoussi
AD et al. Prospective evaluation of late cosmetic
results following breast reconstruction. II. TRAM flap
reconstruction. Plast Reconstr Surg 2001; 107:1710–6.

Chapter 9
152
The tissue from the back is thicker than that of
the native chest skin and the colour match may be
different, and this needs to be taken into consider-
ation. The  procedure generally requires 3–4 hours
operating time, with an extended LD usually taking
longer than an LD and implant, a hospital stay of
5–7 days and a recovery time of 4–8 weeks.
Indications
Indications for this technique include the reconstruc-
tion of large ptotic breasts, if the chest wall tissues
are unsuitable for tissue expansion, or if additional
skin needs to be imported following mastectomy.
Additional indications include chest-wall reconstruc-
tion in locally advanced breast cancer, partial breast
reconstruction after breast conservation surgery, or
for salvage following loss of an abdominal tissue flap.
Contraindications
The LD flap is contraindicated where it is suspected
that previous surgery has damaged the flap pedicle,
such as a thoracotomy or extensive and radical
­axillary surgery, congenital absence of the LD mus-
cle, and significant patient comorbidity. Immediate
LD breast reconstruction, even in the setting of post-
operative radiotherapy, yields satisfactory results.36
Flap options
The LD flap is most commonly used as a musculo-
cutaneous flap with either an oblique or horizontally
Figure 9.7  •  Breast reconstruction using latissimus dorsi myocutaneous flap.
a
b
Figure 9.8  •  Immediate right breast reconstruction
with extended LD flap, a very small implant and nipple
reconstruction.
Figure 9.9  •  Immediate right breast reconstruction
by autologous latissimus dorsi flap after skin-sparing
mastectomy. Courtesy of Eva M. Weiler-Mithoff.

Breast reconstruction
153
orientated skin paddle. A muscle-only flap can be used
where no additional skin is required, and where only
skin is required, a muscle-sparing or thoracodorsal
artery perforator flap may be used.37–40
Preoperative planning
It is necessary to confirm the presence of the LD
muscle prior to surgery by asking patients to push
down onto their hips and palpate the anterior axil-
lary fold for muscle contraction. This is also particu-
larly important following previous axillary surgery
to indicate that the pedicle is likely to be intact, as
the nerve lies in close proximity. Next it is important
to decide how much skin needs to be replaced and
to test the amount of skin that can be taken from the
back whilst allowing closure of the donor site, tak-
ing into account skin-fold thickness. This is usually
between 6 and 9 cm in width, with a lesser amount
of skin taken in high risk patients such as smokers to
reduce the risk of wound breakdown, and approxi-
mately 20 to 25 cm in length. In our experience us-
ing the extended LD flap, the total volume in a lean
back can be expected to be approximately 200 cc,
an average back 400–700 cc, and a variable amount
more can be harvested in larger backs.
Surgical technique
The patient is positioned in the lateral decubitus
position and secured with well-padded table attach-
ments with the arm supported with attachments at
90°. Infiltration of the incision lines is performed
using local anaesthetic with adrenaline to reduce
postoperative pain, induce haemostasis and facili-
tate location of Scarpa's fascia through tissue tu-
mescence where an extended LD flap is planned.
The plane of dissection in an extended flap is imme-
diately deep to Scarpa's fascia to preserve the blood
supply to the back skin and it can be difficult to
locate in some patients. In this situation it is easi-
est to start with the caudal flap, where it is usually
better defined. Additional areas of subcutaneous fat
harvest including the parascapular area, fat anterior
to the anterior border of the muscle and supra-iliac
fat deposits are included in the extended flap.
The anterior border of the LD muscle is usually iden-
tified first. The muscle can then be raised from cepha-
lad, posterior and inferior. Dissection then proceeds
under the anterior border with care to avoid inadver-
tently including slips of serratus anterior muscle with
the flap and the thoracodorsal neurovascular pedicle
and the serratus branch, which can allow retrograde
flap perfusion if the thoracodorsal pedicle has been
previously damaged, are identified and preserved.
The posterior part of the tendon insertion into the
­intertubercular groove of the humerus may be divided
to allow additional mobility to the flap if required. A
high axillary tunnel is fashioned to allow transposition
of the flap whilst avoiding the risk of lateralisation of
the flap into the axilla. Flap haemostasis is checked
prior to transfer anteriorly, and the flap is transferred
to the mastectomy wound, with care not to twist the
pedicle. It is also important to check that there is ad-
equate room for the pedicle without risk of compres-
sion prior to transfer – four finger breadths is usually
adequate. On occasions where additional reach is re-
quired, the humeral insertion can be divided fully or
the serratus branch ligated. Some surgeons divide the
thoracodorsal nerve routinely at the level of the pedi-
cle by excising a segment to avoid postoperative mus-
cle twitching and flap animation and although it was
thought that denervation may decrease the flap bulk
over time due to atrophy. Recent studies have shown
no volume loss over time. Muscle twitching also tends
to decrease with time in those where the nerve is pre-
served and is rarely a problem. The donor site may be
quilted to reduce the tension on the closure and re-
duce the risk of seroma, drains are inserted, and the
wound is then closed in three layers. The patient may
then be repositioned in a supine position for flap inset.
The flap is then sutured and shaped to create a breast
mound, drains are inserted and the skin is closed in
layers. The flap should be sutured to the base of the
mastectomy flaps rather than the chest wall.
The patient is encouraged to wear a well-supporting
brassiere for 6 weeks postoperatively. Physiotherapy
may be instituted to help with shoulder rehabilitation.
Complications
Early postoperative complications include haematoma,
infection, breast skin necrosis, partial or complete flap
failure, or wound breakdown. Late complications in-
clude seroma, implant rupture and capsular contrac-
ture. Seroma formation may be reduced by quilting
sutures at the donor site, and once established may be
reduced by the use of intracavity steroid injections.41,42
Several strategies have been suggested
in order to reduce the incidence of postoperative
seroma following LD harvest. The use of quilting
sutures has been shown to reduce significantly the
risk of seroma formation, and once established
the use of intracavity steroid injections following
aspiration has been shown to significantly reduce
the risk of reaccumulation.41,42

Chapter 9
154
The silicone issue
In the UK the Independent Review Group in 1998
concluded in an exhaustive report that silicone breast
implants are safe, and no new contradictory evidence
has arisen since the publication of the report.50
Breast reconstruction with lower
abdominal tissue
The lower abdominal pannus is usually an excellent
source of tissue for autologous breast reconstruc-
tion and leaves an acceptable donor scar as well as
serving as a simultaneous aesthetic abdominoplasty
(Fig. 9.10). This technique achieves aesthetically sta-
ble results that are stable with time24,51 (Fig. 9.2). It
must be acknowledged, however, that there is a risk
of donor-site bulge and hernia with any technique
that transgresses the anterior rectus sheath.52,53
Indications
Lower abdominal tissue can be used for immediate
or delayed breast reconstruction in any patient with
sufficient tissue. For a microvascular procedure pa-
tients need to be surgically fit. Due to the versatility,
resemblance to a normal breast and excellent long-
term outcome, lower abdominal flaps have become
the first choice for breast reconstruction for many
surgeons.
Contraindications
The only absolute contraindications are previous
ligation of the flap pedicle or previous ­abdominoplasty.
Multiple abdominal scars are a relative contraindi-
cation, as is previous abdominal liposuction, and
imaging of the vascularity may be indicated in these
cases. Midline abdominal scars may necessitate har-
vest of only a hemiflap, or use of a bipedicled flap
in certain circumstances. The most predictable and
safest outcomes after prior breast irradiation involve
the use of autologous tissue, and where radiotherapy
is anticipated to follow immediate breast reconstruc-
tion, autologous tissue is the current accepted stan-
dard due to its better tolerance of irradiation.14,26
Surgical techniques
The lower abdominal pannus receives its dominant
blood supply from perforators of the deep inferior
epigastric artery, a branch of the external iliac ar-
tery, through the rectus abdominis muscle. This ves-
sel connects through reduced calibre vessels within
the muscle with the deep superior epigastric artery,
the terminal branch of the internal mammary artery,
which is the blood supply to the pedicled flap, and
this flap therefore necessitates inclusion of the mus-
cle and the venous drainage is retrograde. The lower
abdominal flap also receives a variable contribution
from the superficial inferior epigastric artery (SIEA),
which lies superficial to the anterior rectus sheath.
The triple blood supply to the lower abdominal
tissue allows it to be used in a variety of techniques,
including the pedicled TRAM flap, free TRAM
flap, free deep inferior epigastric artery perforator
(DIEP) flap and free SIEA flap.54–59 The free TRAM
and DIEP flaps utilise the dominant blood supply
and are associated with a reduced risk of flap com-
plications compared with the pedicled TRAM flap.
In addition, the potential to completely or partially
preserve the rectus muscle and its intercostal motor
nerves leads to reduced donor-site morbidity. It is
important, therefore, to take a careful history of the
activities and hobbies of the patient when consider-
ing the most appropriate reconstruction. With any
technique there may always be persistent absence
of sensory recovery in a triangle between the new
umbilicus position and the abdominal scar.
Pedicled TRAM flap
The pedicled TRAM flap relies on blood flow
through the deep superior epigastric vessels within
the substance of the rectus abdominis muscle. The
flap is transferred onto the chest wall through a
large epigastric subcutaneous tunnel that may be
either ipsilateral or contralateral. The contralateral
Ischaemic complications of the LD flap are rare
due to its robust blood supply, with a complete failure
rate of less than 1%, and it is therefore a useful
technique for autologous reconstruction in higher risk
patients.37,43–46 The long-term aesthetic outcome of
the LD flap in combination with an implant is between
those of an implant reconstruction and a purely
autologous reconstruction. The purely autologous
LD flap may withstand adjuvant radiotherapy better
than the LD flap with implant.36,47–49
The Independent Review Group considered
immense amounts of complex evidence and
reached a number of conclusions, including
that there is no histopathological or conclusive
immunological evidence for an abnormal immune
response to silicone from breast implants in tissue,
and that there is no epidemiological evidence for
any link between silicone gel breast implants and
any established connective tissue disease.50

Breast reconstruction
155
pedicle may produce superior aesthetic results be-
cause it reduces the bulge in the epigastrium and
may avoid disruption of the ipsilateral inframam-
mary fold.56 The only absolute contraindication
is previous ­ligation of the deep superior epigastric
artery pedicle. The flap does not require micro-
vascular skills; however, perfusion through the
non-dominant blood supply leads to higher rates
of complications than the free flap, including fat
necrosis. For this reason some surgeons advocate
flap ‘delay’ by ligation of the ipsilateral deep and
­superficial inferior epigastric arteries before trans-
fer, to allow augmentation of the remaining blood
supply, especially in those considered high risk for
flap necrosis, such as smokers and obese persons.
As the full muscle width is required, the donor site
needs to be reconstructed with prosthetic material
and the donor-site morbidity is higher than with
free flap options.56,60 Bilateral pedicled TRAM flaps
may further increase donor-site morbidity.61
Figure 9.10  •  Techniques of breast
reconstruction using abdominal tissue:
(a) pedicled TRAM flap; (b) free TRAM flap;
(c) free DIEP flap. See text for explanation
of abbreviations. Courtesy of Eva M.
Weiler-Mithoff.
a
b
c

Chapter 9
156
Free TRAM flap
In many centres free flaps from the lower abdomi-
nal wall are the first choice in breast reconstruc-
tion with autologous tissue (Fig. 9.11). The deep
inferior epigastric vessels are the dominant blood
supply for a free TRAM flap. The lower abdomi-
nal skin is transferred with a segment of rectus
abdominis muscle and the deep inferior epigas-
tric vessels, which are anastomosed to the recipi-
ent vessels of the subscapular axis or the internal
mammary system. An ipsilateral pedicle will place
the better vascularised tissue towards the mid-
line. Muscle- and fascial-sparing techniques are
now widely used to avoid the need for insertion
of synthetic mesh at the donor site. Due to the
improved blood supply the rate of fat necrosis is
reduced and a larger flap can be safely transferred
compared with the pedicled flap.62 Muscle-sparing
free TRAM flap techniques have demonstrated
reduced donor-site morbidity.63–65 Many large-­
volume centres are reporting total flap failure
rates of around 1%.53
The operation typically requires 6–8 hours operat-
ing time, a hospital stay of 7–10 days and postop-
erative recovery of 2–3 months.
Deep inferior epigastric perforator (DIEP) flap
The DIEP flap spares the whole of the rectus
­abdominis muscle through meticulous dissection
of deep inferior epigastric artery perforators within
the rectus abdominis muscle and preservation of the
intercostal motor nerves (Fig.  9.12). This reduces
the donor-site morbidity when compared with the
TRAM flap.59,66,67 No muscle and little or no fascia
is harvested and mesh is not usually required for
donor-site closure.
Superficial inferior epigastric artery (SIEA) flap
The SIEA flap is based on the superficial inferior
epigastric artery and vein, which arise from the
common femoral artery and saphenous bulb, re-
spectively. Donor-site morbidity from SIEA flap
harvest is minimal as the vessels are dissected at the
level of Scarpa's fascia and the rectus fascia is left
intact.68 The main disadvantage of the SIEA flap
is variability of the SIEA in presence, calibre and
cutaneous territory. Vessels of at least 1 mm in di-
ameter at the level of the inferior incision can be
used safely for flap transfer. The vascular pedicle
is short and therefore the internal mammary re-
cipient vessels are preferred, and flap inset requires
special consideration due to the peripheral loca-
tion of the pedicle. Perfusion of the flap across the
midline is unreliable, and thus its use is limited to
where only a hemiflap is required and for bilateral
procedures.68–71
Techniques
The flaps are harvested through standard abdomi-
noplasty incisions extending laterally to the anterior
superior iliac spines.59,66 Dissection is from lateral to
medial, taking care to identify the superficial inferior
epigastric pedicle. If the artery is of sufficient size, then
a SIEA flap can be harvested, otherwise the superficial
inferior epigastric vein is dissected for a short distance
for use in case of venous compromise later. The perfo-
rators are inspected and if one dominant perforator or
two or three smaller suitable perforators in the same
intramuscular septum can be harvested then a DIEP
flap is harvested with careful intramuscular dissection
of the perforators to the pedicle, which is located on
the underside of the muscle. Where suitable perfora-
tors for DIEP flap harvest are not present, muscle is
Figure 9.11  •  Immediate left breast reconstruction with
TRAM flap and with nipple reconstruction.
Figure 9.12  •  Delayed DIEP flap and nipple
reconstruction.

Breast reconstruction
157
included (as much as is necessary to incorporate the
perforators) and the dissection continues until a pedi-
cle of sufficient length and calibre is obtained. Sensory
nerves to the flap typically run with the perforators
and may be connected to the lateral branch of the
fourth intercostal nerve, although spontaneous recov-
ery of sensation often occurs.5
A two-team approach with simultaneous prepa-
ration of the recipient site and harvest of the flap
works well. The internal mammary vessels are often
preferred and can be approached either through ex-
cision of a segment of the third costal cartilage or
through the interspaces above or below this. The
anastomosis is performed and the flap inset and
drains inserted, with variable de-epithelialisation
depending on the amount of native breast skin that
has been preserved. Because of its often inadequate
perfusion, the part of the flap furthest from the
pedicle (zone IV) is often excised. The abdomen is
closed in layers and the umbilicus retrieved as per
an aesthetic abdominoplasty and drains inserted.
Complications
Early complications include thrombosis of the arte-
rial or venous anastomosis, haematoma, partial or
total flap loss, fat necrosis, wound breakdown, and
infection of prosthetic mesh if used. Late complica-
tions include donor-site bulge or hernia and reduced
abdominal strength (Table  9.1). Overweight (body
mass index 25–29) and obese (body mass index ≥30)
patients have a significantly increased rate of flap and
donor-site complications.73 Smokers have a higher
incidence of mastectomy flap necrosis and donor-site
abdominal flap necrosis and hernia, although not
thrombosis of the anastomosis or flap loss.74
Superior and inferior gluteal artery
perforator flaps
A superior or inferior gluteal artery perforator
(SGAP, IGAP) flap is indicated when the abdominal
donor site is unavailable due to insufficient tissue
or the presence of multiple abdominal scars or if
the patient wants a more inconspicuous donor-site
scar.75–77 The flaps are limited to small-volume re-
constructions and tissue is firmer and less able to
create ptosis than that from the abdomen. The donor
site, however, particularly with the IGAP flap, can
be excellent in well-selected patients and recovery
is shorter than with abdominal flaps. The internal
mammary vessels are preferred for the anastomosis
to aid inset, due to the relatively short pedicle.
Transverse upper gracilis flap
The transverse upper gracilis (TUG) flap utilises a
transverse skin ellipse from the upper thigh, which
is usually discarded in a traditional aesthetic medial
thigh lift, based on musculocutaneous perforators
through the gracilis muscle from the medial circum-
flex iliac artery. As with the gluteal artery perfora-
tor flaps the disadvantages include small volume
and firmer tissue than from the abdomen, but the
donor-site scar is very well hidden and there is good
patient satisfaction.78–80
Alternative free flap donor sites
Alternative options of autologous tissue breast
reconstruction in selected patients without other
suitable donor sites include the anterolateral thigh
The DIEP flap provides the optimal free flap
breast reconstruction in many centres, although
gaining expertise in its harvest requires a significant
learning curve.72 The SIEA flap has the lowest
donor-site morbidity as the rectus sheath remains
intact, but this flap is limited to a hemiflap and
can only be used in selected cases when the
vascular anatomy is suitable. An algorithm is usually
employed where the vessels to the SIEA flap are
inspected first, and if these are not of sufficient
calibre for an SIEA flap then the superficial inferior
epigastric vein is usually dissected for a short
distance for harvest with the flap for secondary
anastomosis should the flap develop venous
congestion. Next the flap is harvested from lateral
towards the midline and the perforators explored. If
perforators of sufficient calibre are found to support
a perforator flap, then a DIEP flap is harvested, and
if not then a TRAM flap is harvested to include the
perforators, with consideration of a muscle-sparing
technique where this can be performed safely.69

DIEP flap
Free TRAM flap
Fat necrosis
10.1
4.9
Partial flap loss
2.5
1.8
Total flap loss
2.0
1.0
Abdominal bulge
3.1
5.9
Abdominal hernia
0.8
3.9
Table 9.1  •  Pooled complication rates for DIEP and free
TRAM flap patients (%)
DIEP, deep inferior epigastric perforator; TRAM, transverse rectus
abdominis myocutaneous.
Modified from Man LX, Selber JC, Serletti JM. Abdominal wall
following free TRAM or DIEP flap reconstruction: a meta-analysis
and critical review. Plast Reconstr Surg 2009; 124(3):752–64.

Chapter 9
158
flap, omentum and Rubens flap based on the deep
circumflex iliac artery. The free contralateral LD flap
may be used in selected cases of ipsilateral congenital
absence.
Finishing touches
Further surgery may be necessary to the reconstructed
breast, the contralateral breast or the donor site of
the autologous reconstruction. Complete breast re-
construction including nipple–areola reconstruction
requires on average 3.3 separate procedures.81
Surgery to the reconstructed
breast
The reconstructed breast may require adjustment in
size or shape by liposuction, excision of fat necrosis,
mastopexy or augmentation. Lipomodelling trans-
fers fat cells that have been harvested by liposuction
into autologous breast reconstructions such as the
autologous LD flap or the DIEP. This technique is
particularly useful for contour irregularities or gen-
eralised volume loss after adjuvant radiotherapy.
Lipomodelling may be used for adding volume to
the reconstructed breast and smoothing out irregu-
larities, and also for preparing the irradiated bed
prior to implant breast reconstruction.82–84 Further
adjustments of the position of the breast on the
chest wall, improvement of projection, adjustment
of the inframammary fold or revisional surgery for
capsular contracture may be necessary.
Surgery to the contralateral breast
Symmetrising surgery may be achieved by mastopexy,
reduction or breast augmentation. Augmentation is
particularly useful for gaining symmetry where im-
plant breast reconstruction has been utilised. Some
patients may want a contralateral risk-reducing mas-
tectomy with reconstruction where they are deemed
at high risk of contralateral breast cancer after a for-
mal assessment of genetic risk.85
Surgery to the flap donor site
Scar revision, liposuction, lipofilling, treatment of
persistent seroma, correction of dog ears or repair
of an abdominal bulge or hernia may be necessary.
Nipple–areola reconstruction
The breast reconstruction is not complete until
the nipple–areola complex (NAC) has been recon-
structed, although some patients may be happy
with a customised prosthetic nipple alone.86 NAC
reconstruction is usually the last step of the re-
construction as its position is difficult to alter.
The aims of NAC reconstruction are to achieve
symmetry with the contralateral NAC in terms of
size, colour, texture, position and projection (see
Figs  9.3, 9.8 and 9.11). The ideal NAC recon-
struction technique has not yet been discovered, as
evidenced by the number of techniques that have
been described, mainly as a result of loss of projec-
tion with time.87
Nipple reconstruction techniques can be broadly
catagorised as either composite grafts from the op-
posite breast or local flaps. Nipple-sharing is ideal
for women with a large, ptotic contralateral nipple;
however, this causes morbidity to the normal nip-
ple, the graft may fail and there is poor long-term
projection. Almost all local flaps suffer some loss
of projection over time, usually at a rate inversely
proportional to the thickness of the tissue used to
create them, and for this reason overcorrection of
flaps is usually performed. The use of autologous
or prosthetic implants has also been described for
placement within the local flap construct in an at-
tempt to increase longevity of projection.
Areola reconstruction can be performed by full-
thickness skin grafting or by tattooing. Grafts are
usually obtained from the contralateral areola or
the labia majora, with the aim to match the pig-
mentation and texture of the contralateral areo-
lar as closely as possible. For this reason, where
the contralateral areola is not suitable, tattoo-
ing is usually preferred. It is a quick and simple
technique with minimal morbidity and very few
complications apart from fading with time, and
may be performed either before or after the nipple
reconstruction.88
Patients should be offered nipple–areola
reconstruction as an integral part of their
reconstruction. It completes the reconstructed
breast, leads to increased satisfaction with the
reconstruction, a sense of completeness and an
enhanced sense of attractiveness, especially when
the patient is unclothed.86

Breast reconstruction
159
Complications of breast
reconstruction
Mastectomy skin flap necrosis can be a common
complication of immediate breast reconstruction.
Management may be conservative with dressings
if small, or the area can be excised and closed by
advancement of the skin flap or autologous flap
skin paddle, or by split skin grafting. Partial autolo-
gous flap failure usually requires debridement and
management involves dressings, excision, and pos-
sibly skin grafting, but complete flap loss requires
removal of the flap and either direct closure of the
skin flaps, or placement of a tissue expander or im-
plant, or immediate LD flap breast reconstruction,
depending on the patient's wishes. Implant infection
can sometimes be salvaged by washout and reinser-
tion of the implant, but severe infection or extrusion
usually requires removal of the prosthesis (Fig. 9.13)
and replacement at a later date once the tissues are
healed and free from infection. Contour defects fol-
lowing fat necrosis, muscle atrophy or following
radiotherapy may be corrected either by prosthetic
augmentation or by lipomodelling.
Local recurrence
Salvage surgery for chest-wall recurrence is best
dealt with in a multidisciplinary setting. The aims
of surgery are local control of disease, palliation
of symptoms and enhancement of the quality of
remaining life. Chest-wall reconstruction may be
required, and importation of well-vascularised
­non-irradiated flap tissues may allow for further
radiotherapy. Reconstruction of the resultant defect
often requires extensive surgery utilising local flaps
or abdominal advancement, regional flaps such as
LD, pectoralis major and parascapular flaps, omen-
tal transposition, pedicled or free abdominal flaps,
or a combination of these techniques.19,20,89,90
Summary
The aim of breast reconstruction is to recreate the
natural breast as closely as possible following mas-
tectomy. Decisions regarding breast reconstruction
are best made by the fully informed patient within
the setting of a multidisciplinary breast cancer team
that can deliver the oncological surgery as well as
the full range of commonly used breast reconstruc-
tion techniques. Breast reconstruction leads to a
high degree of satisfaction but high levels of preop-
erative information and psychological support are
necessary.91 Close collaboration between oncologi-
cal and reconstructive surgeons or management by
an oncoplastic surgeon and careful patient selection
and counselling can achieve excellent outcomes for
breast reconstruction in the majority of patients.
Figure 9.13  •  Infected prosthesis after right breast
reconstruction that required removal.
Key points
• Breast reconstruction plays a significant role in the woman's physical, emotional and psychological
recovery from breast cancer.
• Even the best reconstruction will not be able to replace the natural breast that has been lost.
• Surgical options for reconstruction include the use of tissue expanders or breast implants and the
use of autologous tissue.
• The most commonly used surgical techniques are tissue expansion, LD musculocutaneous flap
with or without implant, lower abdominal tissue and other free tissue transfers.
• Implant-based techniques require limited surgery initially but have limitations and are not always
quick and trouble free. The quality of the long-term result is directly related to the tolerance of
breast implants but is often disappointing unless performed after bilateral mastectomy.

Chapter 9
160
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• Further procedures are often required for complications and maintenance. Asymmetry may reoccur
due to the effects of gravity on the contralateral breast and fluctuations in body weight.
• The aesthetic results from autologous reconstruction are superior to those of implant-based
reconstruction due to their versatility, more natural appearance, consistency and durability.
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41. Dancey AL, Cheema M, Thomas SS. A prospective
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combination of fibrin sealant and marginal quilting su-
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hospital stay and seroma formation. The authors cau-
tion that potential, albeit small, risk of virus transmission
and allergic reaction, however, needs to be taken into

Chapter 9
162
consideration with the use of fibrin sealant, as with any
blood transfusion product.
42. Taghizadeh R, Shoaib T, Hart AM, et  al. Triamci­
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This prospective study involved 52 extended LD breast
reconstructions in 49 patients, with patients exhibiting
seromas at their first postoperative visit randomised to
receive either intracavity triamcinolone 80 mg or saline
following seroma aspiration. Triamcinolone significantly
reduced the need for any further aspiration, total num-
ber of aspirations, total volume aspirated and total time
to dryness. Steroid injections were well tolerated and
there were no infective complications.
43. Kroll SS, Baldwin B. A comparison of outcomes us-
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46. Hammond DC. Latissimus dorsi flap breast recon-
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any link between silicone gel breast implants and any
established connective tissue disease.
51. Clough BC, O'Donoghue JM, Fitoussi AD, et  al.
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60. Atisha D, Alderman AK. A systematic review of ab-
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62. Kroll SS, Gherardini G, Martin JE, et al. Fat necro-
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63. Nelson JA, Guo Y, Sonnad SS, et  al. A com-
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64. Wu LC, Bajaj A, Chang DW, et al. Comparison of
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65. Bajaj AK, Chevray PM, Chang DW. Comparison
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66. Granzow JW, Levine JL, Chiu ES, et al. Breast re-
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68. Grotting JC. The free abdominoplasty flap for im-
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69. Chevray PM. Update on breast reconstruction using
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71. Selber JC, Samra F, Bristol M, et al. A head-to-head
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164
10
Daniel Xavier Choi
Monica Morrow
Breast cancer: treatment of uncommon diseases
Introduction
This chapter discusses uncommon diseases of
the breast and treatments thereof. These include:
(i) pregnancy-associated breast cancer; (ii) male
breast cancer; (iii) Paget's disease of the breast;
(iv) other breast malignancies, including melanoma,
lymphoma, angiosarcoma and metastases.
Pregnancy-associated
breast cancer
Pregnancy-associated breast cancer (PABC) includes
breast cancer diagnosed during pregnancy, up to
1 year after delivery, or during lactation. PABC is
rare; it constitutes 0.2–3.8% of all breast cancers,
occurring in 1 in 10 000 to 1 in 3000 pregnancies.1
Nonetheless, PABC is the second most common ma-
lignancy in pregnant women (cervical cancer is the
most common). As more women delay childbear-
ing, the incidence of PABC may increase.2
Age for age, compared to non-pregnant women
with breast cancer, pregnant women with breast
cancer tend to be diagnosed at later stages.3 The ae-
tiology of this phenomenon is unclear. One possible
explanation is that PABC may have a more aggres-
sive biology. Alternatively, the significant anatomi-
cal and physiological changes in the breast during
pregnancy may delay diagnosis.
Pathology
Histologically, PABC and non-PABC are similar.
Compared to non-PABC, PABC tends to be
­oestrogen- and progesterone-receptor negative, while
data on expression of human epidermal growth fac-
tor receptor (HER-2)/neu are conflicting.4,5 PABC
stains strongly for Ki67 and p53; the clinical signifi-
cance of these findings is undetermined.6
Clinical presentation
The majority of PABCs present as a palpable breast
mass. Gravid breasts undergo significant ductal and
lobular proliferation under the influence of elevated
levels of oestrogen, progesterone, prolactin and
chorionic gonadotrophin. Mammary blood flow
increases by 180%; the breast may become nodular
and double in weight and volume.7 Therefore, clini-
cal breast examinations may be difficult, and may
contribute to a delay in diagnosis and consequential
poorer prognosis. Moreover, the differential diag-
nosis of breast mass in pregnant women is broad,
including lactating adenoma, fibroadenoma, cystic
disease, lobular hyperplasia, galactocoele, abscess,
lipoma, hamartoma and PABC; 70–80% of breast
biopsies in pregnant women are benign.8
Because PABC is rare, detailed evaluations of risk
factors for PABC development are lacking. One study

Breast cancer: treatment of uncommon diseases
165
of 383 patients, including 192 patients with PABC,
found that patients with PABC were 300% more likely
to have a family history of breast cancer than age-
matched, non-pregnant, non-lactating counterparts.3
Diagnosis
As in all women, dominant breast masses in ­pregnant
women should be investigated with imaging and
biopsies. While screening mammography is not
­routine for pregnant women, diagnostic mammog-
raphy may be useful and can be performed safely
with the use of abdominal shielding. Despite the
fact that women with PABC are young and have
dense, proliferative breasts, diagnostic mammo-
grams ­detect 78–90% of palpable PABCs.9
Ultrasound is a particularly attractive imaging mo-
dality in the setting of PABC. It does not harbour
teratogenic potential, it distinguishes and character-
ises solid and cystic lesions, and if, clinically, a mass
cannot be distinguished from the normal nodularity
of the gravid breast, it may be useful in excluding
the presence of a suspicious lesion.
As in non-PABC, core-needle biopsy is the pre-
ferred method of diagnosis in PABC and offers
two specific advantages in the work-up of a breast
mass. Because the gravid breast is proliferative, fine-
needle aspiration (FNA) and cytological evaluation
may result in false-positive diagnoses of atypia or
carcinoma. Additionally, benign lesions, i.e. adeno-
mas, cysts or fibroadenomas, may increase in size
during pregnancy. Thus, a core-needle biopsy may
offer definitive benign diagnosis and avoid excision.
However, core-needle biopsy is not without risk.
In addition to bleeding, milk fistulas are known
rare complications.10 Therefore, core-needle biopsy
ought to be used with caution for the diagnoses of
centrally located lesions in lactating women.
Metastatic work-up for non-PABC and PABC are
similar and are guided by clinical stage and constella-
tion of symptoms. Chest radiography with abdomi-
nal shielding is safe. Computed tomography (CT)
scans are generally discouraged due to high radiation
exposure. While magnetic resonance imaging (MRI)
does not utilise ionising radiation – and, in fact, has
been ­utilised in foetal imaging in utero – gadolinium
is known to cross the placenta and to affect foetuses
adversely in animals and is not recommended.5,11 No
studies have investigated the role of position emis-
sion tomography (PET) in pregnant patients; in
fact, pregnancy is often an exclusion criterion. Bone
scans using lower doses of radioisotope have been
performed in pregnant women, but are not generally
recommended.11
Treatment (Fig. 10.1)
Local therapy
In general, treatment should not be delayed by preg-
nancy and should be guided by a multidisciplinary
team consisting of a surgical oncologist, a medical
oncologist and a high-risk obstetrician.
A landmark report of 2565 patients demonstrated
no differences in congenital abnormalities between
pregnant women who did and did not undergo sur-
gery.12 However, surgery during pregnancy was asso-
ciated with an increased rate of spontaneous abortion.
The risk of spontaneous abortion is highest in the first
trimester, and the patient and surgeon may choose to
defer surgery until after the 12th week of pregnancy.
The surgical team must be aware of the physiologi-
cal changes of pregnancy, including increased plasma
volume, increased cardiac output, decreased systemic
vascular resistance, hypercoagulable state, dilutional
anaemia with associated decreased oxygen-carrying
capacity, and delayed gastric emptying. Additionally,
a pillow should be placed on the right side of the
patient to keep the gravid uterus from pressing upon
the inferior vena cava. The foetus should be moni-
tored intraoperatively and postoperatively.
Surgery should be tailored according to the clini-
cal stage of the PABC and the gestational age of
the foetus. Mastectomy can be performed dur-
ing any trimester, although immediate breast re-
construction is not usually recommended due to
the increased operative time and the difficulty of
achieving symmetry with the contralateral breast as
it continues to change during and after pregnancy.
The decision to undertake breast-conserving ther-
apy in the pregnant woman is much more complex.
Breast-conserving therapy is generally not recom-
mended in the first trimester because of a need to
delay radiotherapy until after delivery, increasing

Chapter 10
166
the risk of local recurrence. However, for the pa-
tient who receives adjuvant chemotherapy, this
delay is no longer than that of the non-pregnant
patient. Breast-conserving therapy is feasible in the
second and third trimesters.
Axillary staging
Previously, sentinel lymph node biopsy (SLNB) was
not recommended in gravid or lactating women.
Lymphazurin blue, patent blue V and methylene blue,
the most commonly used dyes, have not been stud-
ied in pregnant women and their safety has not been
established. Technetium-99 m, the most commonly
used radioactive tracer, involves low doses of radiation
(1.85–3.7 MBq). Gentilini et  al. found that sentinel
lymph nodes were successfully identified in all patients,
foetal radiation exposure was minimal and there were
no adverse foetal outcomes.13 Although there are no
medical contraindications to lymphatic mapping with
radioactivity during pregnancy, it remains to be seen if
this procedure will be widely adopted.
Systemic therapy
In general, chemotherapy is contraindicated dur-
ing the first trimester, for it exposes the foetus to
an increased risk of abortion and malformation.
In a small series, Ebert et  al. noted that all the
abortions that occurred in women during preg-
nancy were in those women who had received che-
motherapy during the first trimester of pregnancy;
while chemotherapy during the first trimester re-
sulted in a 14–19% risk of foetal malformation,
chemotherapy during the second trimester resulted
in a 1.3% risk.14 A prospective cohort study of 24
women, who received 5-fluorouracil, doxorubicin
and cyclophosphamide during the second and third
trimesters, found no congenital malformations, or
short- or long-term complications in the infants;
there were no stillbirths, miscarriages or perina-
tal deaths. Except for one child with Down's syn-
drome, the vast majority of infants ­demonstrated
‘normal development’ and eventually grew into
functional school-aged children.15,16
Dominant breast mass
Diagnostic mammogram/ultrasound
Needle biopsy
Benign
Follow clinically
Enlarging
Stable size
No further
treatment
Excisional
biopsy
Cancer
Clinical staging-symptom based
Locally advanced breast cancer
Inflammatory breast cancer
Metastatic breast cancer
Counselling
Individualised
treatment
Counselling
First
trimester
Second and third
trimester
Chemotherapy with FAC, AC or
AC followed by taxane after delivery
MRM
Radiation therapy
after delivery
ER/PR+
Endocrine therapy
after delivery
Chemotherapy with FAC, AC or AC
followed by taxane after delivery
ER/PR+
Individualised
treatment
Stage I and II
All trimesters
of pregnancy
Second and third
trimesters
>10%
recurrence
Counselling
No further treatment
during pregnancy
<10%
recurrence
First
trimester
Mastectomy
Mastectomy or lumpectomy
RT after
delivery
Figure 10.1  •  Management algorithm for the pregnant woman with a dominant breast mass. ER/PR+, oestrogen
and progesterone receptor positive; FAC, fluorouracil, doxorubicin and cyclophosphamide; MRM, Modified Radical
Mastectomy.

Breast cancer: treatment of uncommon diseases
167
During pregnancy, methotrexate should be
avoided due to a risk of associated abnormalities.
A review examining the use of taxanes, vinorelbine
and trastuzumab demonstrated that taxanes and
vinorelbine were safe for mother and offspring in
the limited experience available, but trastuzumab
was associated with anhydramnios in 50% of
cases.17 Endocrine therapy is not recommended dur-
ing pregnancy. Tamoxifen has been associated with
spontaneous abortions, teratogenicity and foetal
demise.18
In general, for women with PABC with positive
lymph nodes, chemotherapy is ideally administered
after the first trimester, but within 6 weeks of sur-
gery. For patients diagnosed early in the first trimes-
ter, this may be impossible. For women with PABC,
negative lymph nodes and low-risk cancers (where
the survival benefit of chemotherapy is 5% or less),
treatment during pregnancy is usually avoided. For
women with PABC also having negative lymph
nodes and high-risk cancers, treatment decisions
must be made on an individual basis. Chemotherapy
ought to be stopped 3  weeks prior to delivery to
avoid myelosuppression and septic complications in
mothers and their offspring.6
Locally advanced and inflammatory
breast cancers
The treatment of locally advanced and inflamma-
tory breast cancers during pregnancy is problem-
atic for women diagnosed during early pregnancy
because of the foetal risks of chemotherapy. Three
strategies exist: first, termination of pregnancy with
prompt oncological treatment; second, administra-
tion of chemotherapy with acceptance of associated
obstetric risks; third, delayed oncological treatment
with acceptance of associated oncological risks.
None of these is ideal, and deciding between them is
difficult. As in non-pregnancy-associated inflamma-
tory breast cancer, surgery as an initial approach to
pregnancy-associated inflammatory breast cancer
should be avoided.
Termination of and future pregnancy
Historically, the prognosis of PABC was considered
so dismal that therapeutic abortion was advocated
for all women. However, compared to women who
terminated their pregnancies, women who contin-
ued their pregnancies did not demonstrate worsened
overall or disease-free survivals.1,5 There are cur-
rently no formal recommendations for therapeutic
abortions in patients with PABC. However, as dis-
cussed, therapeutic abortion can simplify treatment
in patients with locally advanced and inflammatory
breast cancers. Women should be counselled that
chemotherapy may adversely affect future fertility.
Though fertility may be hindered by patient age
and chemotherapy, retrospective studies demon-
strated that pregnancy after diagnosis and treat-
ment of breast cancer was safe. Gemignani et al.
reported that compared to patients treated for
PABC who did not become pregnant, those who
did had equivalent or better survival,1 although
this may be a result of selection bias. A popula-
tion-based study conducted by the Danish Breast
Cancer Cooperative Group found no difference in
survival amongst 371 patients with PABC who be-
came pregnant after treatment and 9865 patients
with PABC who did not.19
Despite the fact that the rate of relapse is fairly
constant for the first 10  years after treatment,
some experts advocate waiting 2–5 years for future
pregnancies,6 contending that this affords a period
during which recurrences can become manifest –
up to 2 years for high-risk cancers, up to 5 years
for low-risk cancers. However, a population-based
report showed that for women with localised dis-
ease and good prognosis, conception 6 months af-
ter completion of treatment was unlikely to reduce
survival.20
Prognosis
Because of the anatomical and physiological
changes of the gravid and lactating breast, PABC
tends to be diagnosed at a more advanced stage. In
one study, fewer than 20% were diagnosed prior
to delivery, median tumour size at diagnosis was
3.5 cm, and 62% of PABC patients had lymph-node
metastases compared to 39% of matched controls.1
Additionally, relative to non-PABC patients, PABC
patients are more likely to have larger tumours, vas-
cular invasion and distant metastasis.4
Historically, it was believed that, compared to
non-PABC, PABC was intrinsically more aggressive
and thereby carried a worse prognosis. However,
recent studies have demonstrated this may not be
correct. A review of 104 PABC and 564 non-PABC
patients demonstrated that PABC had a more ad-
vanced T classification, N classification and stage.21
Moreover, the two groups did not ­demonstrate

Chapter 10
168
any differences in locoregional recurrence, distant
metastases or overall survival. For patients with
PABC, the timing of diagnosis and treatment was
the only factor associated with overall survival;
those who had prompt diagnosis and treatment
had better overall survival than those who had de-
layed diagnosis and treatment. In an older study,
Gemignani et al. found that, for stage I and stage II
disease, PABC and non-PABC patients had similar
survivals.1 However, compared to non-PABC, there
was a trend towards a worse prognosis in stage III
and stage IV PABC. Similarly, with negative lymph
nodes, PABC patients had the same 5-year sur-
vival as non-PABC controls; however, for patients
with positive lymph nodes, PABC and non-PABC
patients had 5-year survivals of 47% and 59%,
respectively.
Male breast cancer (Fig. 10.2)
In the 14th century, John of Arderne, an English
surgeon, reported the first case of male breast can-
cer (MBC).22 He cared for a priest who had progres-
sive nipple–areolar ulceration. Almost certainly he
died of this disease.
In the West, MBC accounts for less than 1% of
all breast cancers and for 0.1% of cancer deaths in
men.23 These rates have remained stable in the sec-
ond half of the 20th century.24 However, rates of
MBC have recently increased.25 Though a complete
explanation is elusive, this is likely due in part to
an increase in the number of men diagnosed with
ductal carcinoma in situ (DCIS) between 1973 and
2001.26 Interestingly, there is an MBC ‘belt’ that ex-
tends from the Atlantic to the Indian Oceans in sub-
Saharan Africa.27 In Tanzania, 6% of breast cancers
are diagnosed in men.
Pathology
Almost all pathological types of breast cancer found
in women have been described in men. Ninety per
cent of MBCs are invasive; of these, 80% are duc-
tal, 5% are papillary and 1% are lobular.28 The
scarcity of lobular carcinoma probably reflects the
paucity of terminal lobular units in male mammary
tissue. Paget's disease of the breast and inflamma-
tory breast cancer are as frequent in men as they
are in women.29 Less common subtypes, i.e. med-
ullary, mucinous, squamous and tubular, have also
been reported in men, but at lower frequencies than
in women. Ten per cent of MBCs are non-invasive;
almost all are DCIS,28 and most are of the papillary
subtype and of low or intermediate grade.30 Lobular
carcinoma in situ is rare.
When matched for age, stage and grade, men
with breast cancer have a higher rate of oestrogen
receptor positivity than women with breast cancer.
A 25-year review of the Surveillance Epidemiology
and End Results (SEER) database, which included
2357 MBCs, demonstrated oestrogen and proges-
terone positivity in 90% and 80% of breast cancers
in men, and in 76% and 67% of breast cancers in
women.31 Data on the overexpression of erbB-2 or
Figure 10.2  •  (a) Mammogram of male breast cancer in right breast. (b) Ultrasound of male breast cancer in
right breast.
a
b

Breast cancer: treatment of uncommon diseases
169
HER-2/neu, p53, bcl-2, cyclin-D1 and epidermal
growth factor receptor in MBC are limited, conflict-
ing and inconclusive.
Clinical presentation
Though MBC can occur at any age, its incidence
increases with age. The average age of diagnosis
of breast cancer in men is approximately 10 years
later than in women. Eighty-five per cent of MBCs
present as a painless mass32 and most MBCs are
centrally located, with up to 50% demonstrating
nipple retraction, discharge, pain or ulceration.33
The time from the onset of symptoms to diagnosis
is longer in men than in women – approximately
22 months. As a result, men often present at later
stages.34
There are multiple risk factors for the develop-
ment of MBC. Hormonal misbalance is one of
these. Men with a history of undescended testes,
congenital inguinal hernia, orchiectomy, orchitis,
testicular injury, infertility, Klinefelter's syndrome,
and obesity and cirrhosis (both of which induce a
hyper-­oestrogenic milieu) are at elevated risk.35,36 In
particular, Klinefelter's syndrome, which is charac-
terised by a 47XXY karyotype, small testes and gyn-
aecomastia, is associated with a 50-fold elevated risk.
Family history is another important risk fac-
tor. Between 15% and 20% of male patients with
breast cancer have a family history of disease. The
odds ratio for MBC increases with a positive fam-
ily history and continues to increase as the num-
ber of affected first-degree relatives increases.37,38
These factors probably reflect an increasing risk of
BRCA1 and BRCA2 mutations, which predispose
both men and women to breast cancer. Previous
reports have focused on the association between
MBC and BRCA2 mutations. However, a recent
report suggests that BRCA1 and BRCA2 carry
equivalent elevations in risk.39 Male BRCA2 muta-
tion carriers have a 6.3% cumulative risk of breast
cancer.37,38 In the United States, 4% of MBCs are
in BRCA2 mutation carriers; in Iceland, where a
‘founder effect’ is present, 40% of MBCs carry a
mutation in BRCA2.37
As in women, radiation exposure is a risk factor
for the development of breast cancer in men.36 One
evaluation of a national database of 324 799 men
without breast cancer and 121 men with breast
cancer found that a history of a bone fracture and
obesity were associated with the development of
MBC; relative risk ratios were 2.2 and 1.79 respec-
tively.40 Though gynaecomastia in and of itself was
once thought to be a risk factor, it is no longer
considered to be.34,36 Indeed, it may be the case
that obesity is associated with both gynaecomastia
and MBC.
Diagnosis
The differential diagnosis of a breast mass in a man
is somewhat limited: gynaecomastia is by far the
most common cause, while abscess, sarcoma and
metastasis are much less common. The work-up
of a breast mass is similar in men and women, al-
though imaging studies are less important in men.
Physical examination characterises the size, shape
and location of a mass, as well as the presence of
nipple discharge or retraction, and skin changes.
Examination of axillary, supraclavicular nodes and
infraclavicular nodes should be performed. A di-
agnostic mammogram and focused ultrasound can
be used to visualise and to characterise the lesion,
but rarely obviates the need for histological diagno-
sis. Since mastectomy is the treatment of choice in
the majority of MBCs, breast imaging is of limited
utility unless a limited excision is planned. As in
women, core-needle biopsy is the diagnostic tech-
nique of choice. Symptoms, laboratory values and
clinical stage should guide the work-up for meta-
static MBC.
Treatment
In a retrospective review, Scott-Conner et al. found
significant differences in the treatment of matched
men and women with breast cancer.41 Given ana-
tomical considerations, compared to women, men
are less likely to undergo breast-conserving sur-
gery. Also, compared to women, men who undergo
breast-conserving surgery are less likely to receive
adjuvant radiotherapy. Men are also less likely to
receive adjuvant chemotherapy.
Local therapy
Surgery – specifically, mastectomy – is the primary
therapy for MBC. Although breast-conserving sur-
gery has been performed for MBC, the minimal
amount of mammary tissue in most men and the

Chapter 10
170
central location of most tumours do not make this a
particularly attractive option. If a tumour is in close
proximity to or involves the pectoralis major, it may
be necessary to resect a small portion of underlying
muscle to ensure a negative margin; there is no lon-
ger a role for radical mastectomy. Locally advanced
disease should be treated with neoadjuvant therapy
followed by mastectomy.
Axillary staging guidelines are similar for men
and for women. If axillary lymph nodes are
clinically negative, SLNB should be performed.
Sensitivity and specificity of SLNB in women and
men are similar.42 Clinically positive nodes should
undergo core biopsy or FNA for histological con-
firmation, which will allow axillary dissection
without an SLNB.
Adjuvant therapy
The same guidelines used to make recommenda-
tions for adjuvant therapy in women with breast
cancer should be used in men. Two comprehensive
reviews confirmed the benefits of adjuvant che-
motherapy and hormonal treatment in MBC.43,44
Although no trials have been conducted to deter-
mine indications for postmastectomy radiation for
MBC, it has been reported to reduce rates of local
recurrence, and guidelines for women are usually
applied for men.45
Treatment of metastatic disease
For hormone receptor-positive metastatic MBC, en-
docrine therapy is the mainstay of treatment. In the
past, ablative surgeries, including orchiectomy, were
used. A variety of hormonal therapies have been
used, including exogenous steroids, androgens, anti-
androgens, oestrogens, progestins, aminoglutethi-
mide and tamoxifen, and may improve survival.46,47
Tamoxifen is the drug of choice. In men, the testes
produce 20% and the periphery produces 80%
of circulating oestrogens. Thus, aromatase inhibi-
tors pose two potential problems in MBC, mitigat-
ing their efficacy. Firstly, they only partially block
oestrogen production. Secondly, decreased levels of
circulating oestrogens induce the hypothalamus to
stimulate testicular hormone production. This may,
in part, account for therapeutic resistance in aroma-
tase inhibitors.48 A 2010 consensus conference con-
cluded that aromatase inhibitors should only be used
in men in conjunction with surgical or medical or-
chiectomy.49 A phase II trial examining the use of an
aromatase inhibitor combined with goserelin acetate
for androgen suppression is ongoing. For hormone
receptor-negative MBC, chemotherapy is the main-
stay of therapy.46
Prognosis
Overall, despite delays in presentation, diagnosis
and treatment, stage for stage, women and men
with breast cancer have the same prognosis, which
continues to improve as new diagnostic methods
and treatments evolve.50–52 The same factors pre-
dict outcome: node status, tumour size and grade,
and hormone receptor status. As for women with
breast cancer, axillary lymph node status – negative
versus positive, and number of positive nodes – is
the most important prognostic factor in men.53 In
a study of 335 cases of MBC, node-negative pa-
tients had a 5-year survival rate of 90%, whereas
node-positive patients had a 5-year survival rate
of 65%.54 Also, 10-year survival for patients with
one to three positive nodes was 44%; with four
or more positive nodes, it was 14%.53 Giordano
et al. reported that, for MBC, rates of 5-year sur-
vival were 76% for grade 1 tumours, 66% for
grade 2 tumours and 43% for grade 3 tumours.31
Patients with oestrogen receptor- and progester-
one receptor-positive tumours had significantly im-
proved survival compared to those with oestrogen
receptor- and progesterone receptor-negative tu-
mours,55 reflecting differences in both biology and
treatment.
Paget's disease of the breast
(Fig. 10.3)
In 1856, Alfred-Armand-Louis-Marie Velpeau, a
French surgeon and anatomist, described a clini-
cal condition in which patients suffered from
bleeding and crusting ulcerations of the nipple
and areola.56 Velpeau believed that this condi-
tion was primarily dermatological in nature, fail-
ing to recognise that more than 95% of women
with what we now know as Paget's disease of the
breast have an underlying malignancy. Nearly
two decades later, Sir James Paget, the British
surgeon and pathologist, described this associa-
tion.57 He described ‘an eczematous change in the
skin of the nipple preceding an underlying mam-
mary cancer’.

Breast cancer: treatment of uncommon diseases
171
Pathology
In Paget's disease of the breast, the epithelium of the
nipple–areola complex displays two characteristic
findings. First, Pagetoid cells are present – the sine
qua non of Paget's disease of the breast. These are
large, round or oval cells with enlarged pleomorphic
and hyperchromatic nuclei, prominent nucleoli and
abundant, clear, pale cytoplasm. Second, reactive
changes in the epidermis and dermis, such as lym-
phocytic infiltration and angiogenesis, are also seen,
giving rise to the hyperaemic, exudative appearance
characteristic of Paget's disease of the breast.58
At present, there are two competing theories as to
the pathogenesis of Paget's disease of the breast. One
suggests that Pagetoid cells are keratinocytes that have
undergone malignant transformation. According to
this theory, Paget's disease of the breast represents an
in situ carcinoma of the skin.59,60 This theory is sup-
ported by the observation that, often, overlying skin
changes and underlying malignancy are discontinu-
ous. Another theory suggests that cells migrate along
basement membranes and enter the epidermis and
dermis of the nipple–areola complex.61 Pagetoid cells
and underlying carcinomas demonstrate similar im-
munohistochemical staining patterns, supporting this
theory that it is cells from the cancer that migrate.62
Clinical presentation
Paget's disease of the breast occurs in both men
and women. However, it is rare, accounting for
0.7–4.9% of breast malignancies.59 Interestingly,
age-adjusted rates of Paget's disease of the breast
peaked in 1985 and have steadily decreased from
1.31 to 0.64 per 100 000.63 The clear cause of this
epidemiological phenomenon remains elusive, but it
may be the case that as screening programmes are
more widely available, clinically occult breast ma-
lignancies are detected prior to the development of
dermatological nipple–areolar changes.
The first symptomatic manifestations are sensory –
for example, lymphocytic infiltration and angio-
genesis, which can produce burning or itching.
Dermatological changes follow – crusty, erythema-
tous flaking, and irregular, raised, scaly skin lesions
may develop. Classically, these start within the nip-
ple, spread to the areola and ultimately spread to
the surrounding skin. This contrasts with eczema,
which starts in the areola. As the disease progresses,
bleeding, ulceration and destruction of the nipple–
areola complex occur. Nipple discharge is rare and
is usually a result of advanced local disease, rather
than a consequence of Paget's disease. In approxi-
mately half of patients with Pagetoid changes of
the nipple, an underlying malignancy is palpable.64
Rarely, the underlying malignancy tethers the nipple–
areola complex or adjacent skin, causing retrac-
tions and deformity of the natural contour of the
breast.
In the absence of a palpable mass – in part be-
cause it is rare and has an innocuous appearance –
misdiagnosis of Paget's disease as eczema and
treatment with topical steroids is common.60,65
Typically, the interval from the development of
symptoms to definitive diagnosis and treatment is
10–12 months.58
Diagnosis
The diagnostic goals for suspected Paget's disease
of the breast are twofold: confirmation that the
Figure 10.3  •  (a) Early Paget's disease. (b) More extensive Paget's disease of the nipple.
a
b

Chapter 10
172
­cutaneous disease is Paget's and the detection of the
underlying malignancy.
Eczematmous changes of the nipple–areola com-
plex in the absence of a history suggestive of contact
dermatitis should be biopsied. A punch biopsy can
be performed and allows sampling of the epidermis,
dermis and subdermis. If non-diagnostic, excisional
biopsy is more invasive, but provides more tissue.
Histology reveals Pagetoid cells. On immunohisto-
chemistry, these cells stain for CK7, CAM-5.2, AE1/
AE3 and S100; they do not stain for HMB-45 or
keratins, differentiating them from melanoma.66
Almost 90% of Paget's cells are HER-2 positive.
As with all breast cancers, bilateral ­mammography
and ultrasound are the initial steps in the ­imaging
work-up. If a lesion is seen, it is investigated in
standard fashion. However, the sensitivity of mam-
mography in this setting is limited; in one series,
mammography detected only 32% of underlying car-
cinomas.67 Breast MRI may be valuable in diagnosing
clinically and mammographically occult underlying
malignancies in patients with Paget's disease of the
breast, with case reports and series demonstrating
identification of carcinomas.68,69 In a series of eight
cases with a normal mammogram, MRI identified an
underlying carcinoma in half.67 Moreover, Morrogh
et al. showed that MRI demonstrated the extent of
occult disease in six of seven patients, thereby guid-
ing surgical planning and the decision whether to
pursue total mastectomy or breast conservation.67,70
Treatment (Table 10.1)
Surgery is the mainstay of treatment for Paget's
­disease of the breast – except for patients with
­significant comorbidities. For all patients, resection
of the nipple–areola complex is necessary; small
studies have demonstrated that preservation of the
nipple–areola resulted in unacceptably high rates of
local recurrence.71 In patients with an identifiable pri-
mary tumour, the choice between total mastectomy
and central lumpectomy is determined by the extent
of disease. If disease is confined to the central breast,
multiple small studies have demonstrated low rates
of local recurrence after excision to negative margins
and adjuvant radiotherapy. After a median follow-up
of 6.4 years, one prospective study of 61 patients dem-
onstrated a local recurrence rate of 5.2% after central
lumpectomy to clear margins and 50 Gy of adjuvant
radiotherapy.72 When cancer is present at a distance
from the nipple–areola complex, mastectomy is the
treatment of choice. In the absence of an identifiable
tumour within the breast, Paget's disease is consid-
ered to be ductal carcinoma in situ of the nipple–­
areolar region and can be treated with excision alone
or excision and radiotherapy. In one small study of 48
patients, 40% of patients with Paget's disease of the
breast treated with excision alone experienced a local
recurrence after 4.6 years of median follow-up.65
Axillary staging with SLNB is performed when
invasive cancer is present or if mastectomy is under-
taken without a diagnosis of invasive cancer.
Guidelines for systemic therapy for women with
and without Paget's disease of the breast are identical.
Prognosis
The underlying malignancy and the treatment
thereof determine the prognosis of patients with
Paget's disease of the breast.73
Reference
Year
n
Median
follow-up
(months)
Radiation
Recurrence
(%)
No. of
local
recurrences
No. of distant
recurrences
No. of
deaths
Kawase et al.74
2005
12
84
Yes
8
1
0
0
Marshall et al.75 2003
36
113
Yes
11
4
0
0
Bijker et al.72
2001
61
77
Yes
5.2
4
2
1
Fu et al.71
2001
12
42
No
25
3
0
0
Kollmorgen
et al.76
1998
10
71
No
20
0
2
2
Dixon et al.65
1991
10
56
No
40
4
0
0
Fourquet et al.77 1987
20
90
Yes
6.7
3
0
0
Table 10.1  •  Conservative management of Paget's disease of the nipple

Breast cancer: treatment of uncommon diseases
173
Other breast malignancies
Melanoma of the breast
Constituting 0.28% of all primary melanomas,
primary melanoma of the breast is exceedingly
­infrequent.78 Melanoma is more likely to ­present
in the breast as a result of a metastasis from a
­non-mammary primary tumour.79
The investigation and treatment of melanoma of
the breast is similar to the investigation and treat-
ment of melanoma elsewhere. The history should
focus on risk factors for its development – including
cancer history, sun exposure and family history –
and on changes in size or shape, ulceration or
­bleeding, and the presence of satellite, in-transit or
distant lesions. Physical examination should include
a comprehensive skin survey as well as examination
of all nodal basins. Because it is a cutaneous lesion,
mammography and ultrasound are generally not
helpful in diagnosis or therapeutic planning. Rather,
core-needle, punch or surgical biopsy of the thick-
est portion of the lesion should be performed, first
to establish the ­diagnosis and second to determine
the depth of invasion. Immunohistochemistry for
HMB-45 and S100 may help differentiate melanoma
from other cutaneous lesions. A thick ­lesion should
prompt staging assessment, which may ­include mea-
surement of serum lactate dehydrogenase (LDH)
and imaging with CT, MRI or PET. Staging fol-
lows guidelines from the American Joint Committee
on Cancer (AJCC) or International Union Against
Cancer (UICC).
Surgical excision is the primary treatment for mel-
anoma of the breast. In the past, mastectomy was
considered the procedure of choice. Currently, it is
recommended that patients undergo wide-local exci-
sion to margins determined by the depth of the le-
sion. SLNB is indicated for thin melanomas with poor
prognostic features and for all intermediate and deep
melanomas.80 Clinically positive nodes and positive
sentinel nodes should prompt axillary dissection.
Adjuvant treatment for primary melanoma of the
breast follows current guidelines for adjuvant treat-
ment of melanoma elsewhere.
Primary breast lymphoma (Fig. 10.4)
Primary breast lymphoma (PBL) constitutes 0.14%
of all breast malignancies and 0.60–2.00% of
all non-Hodgkin's lymphomas. It arises from
­mammary lymphoid tissue and, by definition, is lo-
calised to the breast and its draining lymph node
basins.81,82 The most common subtype is diffuse
large B-cell lymphoma.81,82 PBLs are categorised us-
ing the Working Classification and the Ann Arbor
Classification of lymphomas.
The mean age of patients with PBL is 65 years.81,82
These lesions often present as a painless, enlarg-
ing and rubbery mass. Because mammographic
and sonographic findings tend to be non-specific,
PBL is usually not suspected (in the absence of
constitutional symptoms) until a core-needle bi-
opsy is obtained. Once the diagnosis is known, a
complete history and physical examination should
be obtained, focusing on constitutional symptoms
and evaluation of lymph node basins. Additionally,
CT of the chest, abdomen and pelvis, and bone
marrow biopsy, are needed for adequate stag-
ing, though according to one pathological review,
gene rearrangement analysis precluded the need for
bone-marrow biopsy and histological evaluation in
certain populations.81
Figure 10.4  •  Mammogram of a primary breast
lymphoma in the subareolar space. The appearance is
indistinguishable from that of a primary adenocarcinoma.

Chapter 10
174
In general, surgery is neither necessary nor recom-
mended for PBL. According to single-institution
reports, surgery either alone or in conjunction
with radiation results in increased rates of local,
regional or distant recurrence, and decreased rates
of survival.82,83 Surgery is no longer indicated for
PBL except for situations in which the core-needle
biopsy proves to be non-diagnostic. Chemotherapy
directed to the histological type and targeted radio-
therapy are the mainstays of treatment, and have
proven to be modestly effective.84–86 The role of
rituximab continues to be evaluated.87
As with all lymphomas, the International Prognostic
Index is helpful in predicting the aggressiveness of
PBLs.88 The 2-year overall survival of mammary
lymphomas is 63%, which is consistent with the
overall survival of extramammary lymphomas.81
Immunohistochemical studies of PBLs have shown
that tumours co-expressing bcl-6 and CD-10 have a
better prognosis than those that do not.83
Angiosarcoma of the breast
(Fig. 10.5)
Angiosarcoma of the breast is rare, constituting 0.05%
of all breast malignancies.89 Primary angiosarcoma of
the breast occurs sporadically; secondary angiosar-
coma of the breast occurs in the setting of a history
of radiotherapy and lymphoedema.89 For an angio-
sarcoma of the breast to be considered radiotherapy
induced, it must occur within the radiated field and
have a long latency. On average, the time interval from
completion of radiotherapy to diagnosis of angiosar-
coma of the breast is 75 months.90 The first report of
post-radiotherapy angiosarcoma of the breast was in
1981.91 The incidence of angiosarcoma of the breast
may be increasing – and may continue to increase – as
more and more patients with breast cancer undergo
breast-conserving therapy with irradiation.92
Primary angiosarcoma of the breast usually presents
as a mass, while post-radiotherapy angiosarcoma of
the breast usually presents as multifocal, painless,
red, blue, purple or black skin nodules (Fig. 10.5).93
The differential diagnosis of early skin lesions is fairly
broad and includes benign radiation-associated skin
changes, recurrent or de novo adenocarcinoma of the
breast, and melanoma. Interestingly, the right breast
is twice as likely to be affected as the left.88
Generally, mammography, ultrasound and MRI
are not helpful.94 Full-thickness punch, or incisional
or excisional biopsy are diagnostic; FNA is not. Two
molecular markers, factor VIII-related antigen and
CD-34, are positive in most angiosarcomas, distin-
guishing angiosarcomas from other sarcomas.92
Staging of angiosarcomas of the breast mirrors
staging of other sarcomas; it is based on tumour
size, grade and depth. As in other sarcomas, grade
is the most important determinant of prognosis.
Whereas most primary angiosarcomas are low
grade, most radiotherapy-induced angiosarcomas
are high grade.93
Treatment consists of total mastectomy with wide
resection of involved skin. The microscopic extent
of disease is often greater than is clinically evident;
every effort should be made to achieve widely nega-
tive skin margins. Axillary staging is not recom-
mended since most sarcomas do not metastasise to
regional lymph nodes. Adjuvant treatment follows
recommendations for other sarcomas.95 Recent case
reports contend benefit for adjuvant radiotherapy,
and in certain patients it may be considered.89,95
In one study of 58 patients, almost half were dead
at an average follow-up period of 15 months.90 In
another study of 69 patients, the recurrence rate
was 55% at a median follow-up of 40 months; the
overall survival was 61% at 60 months.95 In a third
study of 49 patients, the local recurrence rate was
24% at 35 months, the distant recurrence rate was
58.5% at 34 months and the mortality was 44% at
29 months. These reports indicate that the progno-
sis is poor.
Figure 10.5  •  Appearance of a radiation-induced
angiosarcoma on the inferior-lateral aspect of a breast
treated for invasive ductal carcinoma with lumpectomy
and radiotherapy.

Breast cancer: treatment of uncommon diseases
175
Metastasis to the breast
Metastasis to the breast is uncommon, account-
ing for 0.5–6.6% of breast malignancies.96,97 The
contralateral breast is the most common primary
source.92 Other primary sources include lymphoma,
melanoma, rhabdomyosarcoma and small-cell lung
cancer.79
Physical examination and imaging studies dem-
onstrate masses indistinguishable from primary
mammary carcinoma, although they are often cir-
cumscribed. In most cases, core-needle or excisional
biopsy is preferred over FNA for pathological diag-
nosis since immunohistochemistry and the presence
of an in situ component may play an important role
in differentiating between primary and metastatic
tumours.
Treatment is directed at the primary malignancy.
Prognosis is poor: 80% of patients die within
1 year.79
Key points
Pregnancy-associated breast cancer
• A multidisciplinary approach and patient/family counselling are necessary.
• Mammography, sonography and image-guided biopsy are safe during pregnancy.
• Surgery can be performed during any trimester, though may be safest during the second. Radiotherapy
is contraindicated. Chemotherapy can be given safely during the second and third trimesters.
Male breast cancer
• The investigation and treatment of male breast cancer mirror those of female breast cancer.
• Most male breast cancers are oestrogen receptor positive and the endocrine agent used most
commonly is tamoxifen.
• The use of aromatase inhibitors in men is controversial.
Paget's disease of the breast
• Local treatment of Paget's disease of the breast includes either total mastectomy or central
lumpectomy with adjuvant radiotherapy.
• SLNB is indicated when mastectomy is performed or in the presence of invasive carcinoma.
• Adjuvant treatment is determined by the receptor status of any underlying malignancy.
Other breast malignancies
• The investigation and treatment of other breast malignancies are determined by their pathological
diagnosis.
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179
11
Nicola L.P. Barnes
Nigel J. Bundred
Treatment of ductal carcinoma in situ
Background
The introduction of screening mammography has
­resulted in a marked increase in the detection rates of
ductal carcinoma in situ (DCIS) from 2% of newly
diagnosed breast cancers before national screening
to 20% of all screen-detected tumours.1 DCIS is a
preinvasive breast cancer; the proliferation of ma-
lignant ductal epithelial cells remains confined by an
intact basement membrane, with no invasion into
the surrounding stroma.2 Over 90% of DCIS lesions
currently diagnosed are impalpable, asymptomatic
and detected by screening. These screening-detected
cases are frequently small (<4 cm) and localised,
and breast-conserving surgery is often possible.
The remaining 10% present symptomatically, with
a palpable breast lump, nipple discharge or Paget's
disease of the nipple. If these symptoms are present,
the underlying disease is often extensive and usually
requires mastectomy.
Risk factors, natural history,
pathology and receptors
Risk factors
Risk factors for the development of DCIS include
a family history of breast cancer, older age at first
childbirth and nulliparity.3 Although breast epi-
thelial proliferation is increased by the use of the
oral contraceptive pill4 and hormone replacement
therapy (HRT), particularly combined oestrogen/­
progestogen HRT for over 5  years,5 there is little
­evidence to date that either the oral contraceptive
pill or HRT increases the risk of DCIS.4 Two
­studies6,7 have reported a relative risk of 1.4 for
the development of DCIS following oestrogen-
only HRT preparations and a relative risk of
1.7–2.3 with ­oestrogen- and progestogen-containing
­preparations.8 In the Women's Health Initiative
study there were 47 cases of DCIS in the HRT group
compared with 37 cases in the control group (hazard
ratio 1.18; weighted P = 0.09). Other studies have
shown no increased risk following HRT use.9,10
Natural history
Although factors that pertain to an increased risk
of developing DCIS have been identified, the natu-
ral history of this heterogeneous disease remains
poorly understood. It is thought that developmental
pathways for low- and intermediate-grade DCIS are
distinct from the development of high-grade DCIS
and can be explained partly by reference to biologi-
cal markers. In the sequence of progression from
normal breast to DCIS, there is a variable loss of
chromosomal heterozygosity dependent on nuclear
grade. Low- and intermediate-grade tumours show
16q loss, whereas there is 17q gain in high-grade
lesions.11 It is likely that low-grade lesions arise
from oestrogen receptor-positive atypical ductal

Chapter 11
180
­hyperplasia (ADH) or lobular intra-epithelial neo-
plasia carcinoma and progress to low-grade oestro-
gen receptor-positive DCIS. High-grade lesions have
no obvious precursor, unless they arise from usual
ductal hyperplasia or ADH that expresses 17q gain.
The progression of well-differentiated/low-grade
DCIS to poorly differentiated/high-grade DCIS or
high-grade invasive cancer is an uncommon event.12
Retrospective studies of low-grade DCIS misdiag-
nosed as benign conditions found that, 20 years after
local excision, approximately 33% had developed
an invasive cancer.14 As not all cases of DCIS prog-
ress to invasive disease, detection by ­mammographic
screening may lead to over-treatment of ‘non-­
progressive DCIS’, i.e. DCIS that would not prog-
ress to invasive disease if left untreated. It was hoped
that breast screening programmes would, after a lag
phase, result in a decreased incidence of invasive
breast cancer, secondary to an increase in detection
and treatment of DCIS. This has not been demon-
strated, as there has been no corresponding decrease
in invasive disease in a recent review of American
screening data although there appears to be a reduc-
tion in grade 3 cancers in women of screening age
over time.15 There is therefore now concern that we
may be over-treating DCIS and in particular ‘low-
risk’ DCIS, and that such lesions may never pose a
threat to a patient's life. Suggestions for alternative
management strategies for these patients range from
endocrine therapy alone (no surgery)16 to, at the
most extreme, ‘watchful waiting’.15 However, what
constitutes ‘low-risk’ DCIS remains undefined.
The recent MAP.3 trial showed that exemestane
reduces DCIS development in a prevention setting.17
A study looking at ADH (which may be a precursor
lesion of low-grade DCIS and has an approximately
fivefold increase in risk of subsequent invasive
cancer) showed that ADH (and by implication,
­low-grade DCIS) has become less common since
women have stopped using as much HRT.18 The
low-grade lesions are the ones that are being poten-
tially over-treated. They are nearly always oestrogen
dependent. Removing the oestrogenic drive, either
following menopause or with the use of aromatase
inhibitors, may allow control of these low-grade
cases so they progress to invasive cancer only rarely.
Stem cells
Recent evidence suggests that the breast has stem
cells that can reconstitute the various cell types
within the breast after trauma. Cancers (includ-
ing DCIS) arise from accumulations of mutations
within stem cells that disrupt their tightly controlled
self-renewal and proliferation processes. Stem cells
have recently been isolated from human DCIS. In
this process, samples of human DCIS tissue have
been separated into single cells and a subset of
these cells (which are putative stem/progenitor
cells) grows, in non-adherent culture conditions,
to form three-dimensional branching structures
(known as mammospheres). Mammosphere growth
is dependent on growth simulation via the epider-
mal growth factor (EGF) and Notch receptor path-
ways.19 The DCIS stem cell paradigm could explain
the development of both multifocal DCIS and local
recurrence. Stem cells could potentially survive after
wide local excision with clear margins and regrow,
which would also explain the ‘identical’ receptor
expression seen in recurrent DCIS as well as early
recurrences seen most often in high-grade DCIS, as
there are more stem cells found in these high-grade
lesions. Potentially, therefore, targeted inhibition of
stem cells could reduce the rate of DCIS recurrence.
Pathology
Classification and features
DCIS has been classified into two major subtypes
according to the presence or absence of comedo
necrosis. DCIS is designated as comedo if atypical
cells with abundant luminal necrosis fill at least one
duct. In comedo, DCIS cells are large with pleo-
morphic nuclei and abnormal mitoses. The necrotic
material often calcifies and this is what is visible on
mammography.
A review of DCIS recurrences and their primary
lesions from the EORTC 10853 trial12,13 found
concordant histology (similar grade) in 62% of
cases, and identical marker expression (oestrogen
receptor, progesterone receptor, p53 and c-erbB-2/
HER-2/neu) in 63% of both invasive and non-
invasive recurrences.12 This high percentage of
tumours with identical receptor profiles indicates
that it is likely that residual disease after initial
treatment recurs as detectable DCIS or progresses
to invasive cancer.

Treatment of ductal carcinoma in situ
181
Non-comedo DCIS encompasses all other sub-
types and includes the following types:
• Solid – where tumour fills extended duct spaces.
• Micropapillary – where tufts of cells project into
the duct lumen perpendicular to the basement
membrane.
• Papillary – where the projecting tufts are larger
than in the micropapillary type and contain a
fibrovascular core.
• Cribriform – where the tumour takes on a
fenestrated/sieve-like appearance.
• Clinging (flat) – where there are variable
columnar cell alterations along the duct
margins. (There remains controversy as to
whether clinging DCIS is truly an in situ cancer
or whether it should be considered as atypical
hyperplasia rather than DCIS.)
Rarer subtypes also exist, including neuroendo-
crine, encysted papillary, apocrine and signet cell.
The UK- and EU-funded breast screening pro-
grammes classify DCIS as of low, intermediate and
high nuclear grade. This definition is based on the
characteristics of the lesion as seen with a high-
power microscope lens (×40) and uses a compari-
son of tumour cell size with normal epithelial and
red blood cell size:20
• Low nuclear grade DCIS has evenly spaced
cells with centrally placed small nuclei and few
mitoses and nucleoli that are not easily seen.
• High nuclear grade DCIS has pleomorphic
irregularly spaced cells with large irregular
nuclei (often three times the size of
erythrocytes), prominent nucleoli and frequent
mitoses. It is often solid with comedo necrosis
and calcification.
• Intermediate-grade DCIS has features between
those seen in low- and high-grade DCIS.
If a lesion contains areas of varying grade, it is
awarded the highest grade present. A universally
agreed classification system is yet to be established and
will need to be observer independent and clinically rel-
evant. The majority of DCIS lesions are high grade.
Most cases of DCIS are unicentric.21 Following
extensive pathological sectioning of DCIS mas-
tectomy specimens, only 1% show multicentric
disease.21 A multicentric tumour is defined as
separate foci of tumour found in more than one
breast ­quadrant, or more than 5 cm away from
the initial primary. A tumour is classified as mul-
tifocal if there are separate tumour foci in the
same quadrant that are close to each other, al-
though most such lesions have similar morphol-
ogy and are linked.22 The local spread of DCIS
is along branching ducts that form the glandu-
lar breast. The ducts, which are ill defined, often
extend beyond the borders of a quadrant. Most
DCIS is continuous along the branching ductal
network. Poorly differentiated high-grade lesions
are reported to be more frequently ­multifocal.23
Most DCIS recurrences are at or near the site of
the initial tumour,24 but some recurrences are re-
mote from the initial lesion yet exhibit similar ge-
notypical and phenotypical characteristics to the
primary lesion.12
As well as documenting pathological type and
grade on the histology report, the pathologist
should detail the presence or absence of microin-
vasion. If microinvasion is detected histologically,
a thorough examination of the entire specimen
should be undertaken to exclude other previously
unnoticed areas of invasive cancer. Lesions that can
be mistaken for microinvasion include DCIS involv-
ing lobules, branching of ducts, distortion of ducts
by acini or fibrosis, crush or cautery artefacts, and
DCIS involving a benign sclerosing process (e.g. ra-
dial scar).25–29
Lobular intraepithelial neoplasia (LIN)
The current classification combines lobular car-
cinoma in situ (LCIS) and atypical lobular hy-
perplasia (ALH) into a single entity known as
lobular intraepithelial neoplasia (LIN). Rather
than a premalignant lesion, LIN is considered a
marker of increased risk. It is often an incidental
finding during breast biopsy and accounts for
approximately 0.5% of symptomatic and 1% of
screen-detected tumours. In situ ductal and lob-
ular tumours show different pathological and
clinical features. Compared with DCIS, patients
developing LIN tend to be younger and pre-
menopausal, and have bilateral and multicentric
disease of lower grade and close to 100% oes-
trogen receptor expression (Table  11.1). There
is an approximate eight- to ninefold increased
risk of developing invasive carcinoma after a di-
agnosis of LCIS compared to the general popu-
lation.30 Sometimes it is difficult to distinguish
histologically between LCIS and DCIS, and the

Chapter 11
182
pathology report should state this. The clini-
cal interpretation of the report should take into
account the increased risks from both tumour
subtypes.
If LIN is detected at core biopsy, the area of sus-
picion is usually excised to confirm the diagnosis
and exclude an adjacent invasive focus. If LIN is
diagnosed coincidentally following excision of a
coexisting lesion, no further surgical treatment is
necessary (even if the area of lobular neoplasia
is not fully excised) and the patient should un-
dergo regular review on a ‘watch and wait’ basis
or be considered for a preventional strategy. The
NSABP P-1 prevention trial showed a 56% reduc-
tion in the risk of developing subsequent invasive
cancer in women with LCIS who received tamoxi-
fen.31 Further studies are ongoing with aromatase
inhibitors in postmenopausal patients with LIN.
Chemotherapy and radiotherapy have no place
in the treatment of lobular neoplasia. A problem
area is pleomorphic LCIS. The current perspective
is that this should be treated like DCIS rather than
lobular neoplasia but the scientific basis for this
is minimal. Further studies and clarification of
the behaviour and most appropriate treatment of
pleomorphic LCIS is needed urgently.
Receptors and markers
To advance our understanding of the development
and behaviour of DCIS, there has been interest
in cell receptor expression and signalling path-
ways controlling growth. These studies have been
mainly based on immunohistochemical assessment
and show that poorly differentiated high-grade
comedo DCIS has low oestrogen receptor expres-
sion, high rates of cell proliferation32 (as expressed
by Ki67, a nuclear antigen expressed in late G1 S,
G2 and M phases of the cell cycle but not in the
quiescent G0),33 high rates of apoptosis,34 and
over-expression of HER-2 and epidermal growth
factor receptor (EGFR (HER-1)).32 Low-grade le-
sions in contrast have high oestrogen receptor ex-
pression, with lower rates of cell proliferation32
and apoptosis than high-grade lesions,34 and they
rarely overexpress HER-2.32 Progesterone receptor
expression correlates with oestrogen receptor ex-
pression in both low- and high-grade tumours.32 In
comparison, normal breast epithelium has low lev-
els of expression of oestrogen receptor and proges-
terone receptor,35 and a very low rate of apoptosis
and HER-2 expression.
The increased rate of apoptosis seen in DCIS
is lost on progression to invasive cancer, but the
high proliferative rate is maintained.36 Cyclin D1,
an oncogene responsible for G1 cell cycle prolif-
eration/progression and induction of apoptosis,
is overexpressed in approximately 90% of in situ
and invasive ductal cancers.37 It also appears to
be associated with a loss of differentiation (mea-
sured by p27Kip1).38 In oestrogen receptor-positive
tumours, the driving force behind this increase
in cell proliferation is the nuclear action of the
activated oestrogen receptor, which increases
growth-promoting gene transcription. In oestro-
gen receptor-negative DCIS, the driving pathway
is thought to be predominantly via EGFR/HER-2/
RAS/MAP kinase activation (Fig. 11.1). This leads
to a subsequent increase in transcription of both
proliferative and, via Akt, anti-apoptotic genes.
Activation of this pathway also induces the ex-
pression of cyclo-oxygenase-2 (COX-2), which
is an inducible enzyme that converts arachidonic
acid to prostaglandins. It has been found to be
overexpressed in up to 80% of DCIS.39 COX-2-
positive DCIS shows increased cell proliferation,
Clinicopatho-
logical feature

DCIS

LCIS
Age at diagnosis
(years)
54–58
44–47
Premenopausal
30%
70%
Absence of clinical
signs
90%
99%
Mammographic
findings
Microcalcifications
None
Multicentric disease 30%
90%
Bilateral disease
12–20%
90%
Histological grade
65% high grade
90% low grade
Oestrogen receptor
status
65% positive
95% positive
Subsequent
invasive disease
30–40%
25–30%
Ipsilateral–
contralateral ratio
9:1
1:1
Table 11.1  •  Comparative clinicopathological features
of ductal carcinoma in situ (DCIS) and
tabular carcinoma in situ (LCIS)

Treatment of ductal carcinoma in situ
183
and is related to increased tumour recurrence and
decreased survival in invasive cancer.40
In addition to alterations in cell proliferation and
apoptosis, the development of neovascularisation
is necessary for the growth of solid tumours. It
is driven in part by angiogenic factors expressed
in hypoxic areas of the tumour. Hypoxic areas of
DCIS show a less well differentiated, more malig-
nant phenotype, with increased HIF-1α (a hypoxia-
induced transcription factor), decreased oestrogen
receptor expression and increased expression of
­cytokeratin-19 (a breast stem cell marker).27 It is
felt that hypoxia-induced dedifferentiation could
be a factor promoting tumour progression.41
Presentation, investigation
and diagnosis
Presentation
Over 90% of DCIS is detected by mammographic
screening. Approximately 70% of these mammograph-
ically detected cases present as microcalcifications with
no associated mass lesion. Calcifications may be het-
erogeneous, fine, linear, branching, malignant or of in-
determinate appearance. Microcalcifications with an
associated mass lesion are seen in approximately 30%
of DCIS diagnosed by screening.42 Circumscribed
nodules, ill-defined masses, duct asymmetry and ar-
chitectural distortion are sometimes seen in associa-
tion with DCIS.43 When diagnosed clinically, DCIS is
often extensive or associated with a concurrent inva-
sive tumour. It may present as a palpable mass, Paget's
disease of the nipple or nipple discharge.44
Investigation and diagnosis
Thorough clinical examination is important to de-
tect clinical signs of DCIS or coexisting pathology.
In addition to clinical examination (often normal),
ultrasound can be valuable to exclude an associated
mass lesion. Diagnosis is confirmed by core biopsy,
as cytology gives no information on stromal inva-
sion. Image guidance is essential to ensure the ac-
curacy of sampling. Mammographic magnification
views are important in order to delineate accurately
the extent of the microcalcifications.
Stereotactic core biopsy and
vacuum-assisted biopsy
In the NHS Breast Screening Programme, the primary
method of diagnosis was formerly by stereotactic
core biopsy with a 14 G needle. If image-guided core
biopsy was inconclusive then vacuum-assisted biopsy
(VAB) using a device such as a Mammotome, which
takes several contiguous biopsies of a wider calibre
(11 G) during a single pass, can be used. A metal clip
can be inserted during the procedure to aid future lo-
calisation. VAB has a higher sensitivity and ­specificity
than core biopsy and is now the biopsy technique of
choice for microcalcification,45 but still underdiagno-
ses a coexisting invasive tumour in 10–20% of cases
due to sampling error.46 Other factors that have been
Suppression
of apoptosis
Increased cell
proliferation
Angiogenesis
Akt
Gene transcription
Cell cycle progression
MAP K
RAS
HER-2
EGFR
R
TK
R
TK
Figure 11.1  •  The basic growth pathway in oestrogen
receptor-negative breast tumour cells. The oestrogen
receptor-positive signalling pathway is mediated via
oestrogen attaching to its receptor, which then moves
down its concentration gradient to the cell nucleus.
The presence of oestrogen receptor in the cell nucleus
subsequently increases gene transcription and expression
of growth-promoting factors, leading to increased cell
proliferation and tumour growth. In cells that do not
express oestrogen receptors, the main signalling pathway
for growth is via the epidermal growth factor (EGF)/c-
erbB-2 receptor; this activates the RAS intracellular
messenger, which increases cell proliferation and tumour
growth via MAP kinase. RAS stimulation also leads to the
suppression of the apoptosis cascade via Akt and BAD
phosphorylation (an apoptotic protein). MAP K, MAP
kinase; R, receptor; TK, tyrosine kinase.

Chapter 11
184
shown to underestimate the presence of ­associated
invasive disease include high-grade lesions, imag-
ing size >2 cm, Breast Imaging and Reporting Data
System (BI-RADS) score of 4 or 5, a visable mass at
mammography (versus only calcification) and a pal-
pable abnormality.45 If the area of DCIS is extensive
(>4 cm in size), two or more areas should be biopsied
preoperatively to increase the chance of detecting
any associated invasive component.
Localisation-guided biopsy
If a definitive histological diagnosis cannot be made
with core biopsy or VAB, this due to failure to sam-
ple the calcification adequately, or doubt exists as to
whether DCIS is present on histology, then open bi-
opsy is necessary (see Chapter 1). The excised speci-
men should be sent for immediate radiography, after
careful orientation with Liga-clips or metal markers,
to confirm that all microcalcification of concern has
been excised and is clear of margins. The guidelines
of the Association of Breast Surgeons at BASO47 rec-
ommends that 90% of diagnostic guided biopsies
for screen-detected abnormalities should weigh less
than 20 g. Due to improved preoperative diagno-
sis, wire-guided localisation procedures are usually
therapeutic rather than diagnostic. However, DCIS
is often pathologically larger than mammographi-
cally suggested; this is especially true if magnifica-
tion views are not used, and up to 30% of cases need
re-excision to clear margins adequately.48 Accurate
orientation of the specimen is essential to direct re-
excision of the relevant margins and to minimise the
volume of any re-excision.
Other diagnostic procedures
Ductoscopy
Ductoscopy (see Chapter 3) is an appealing option for
DCIS. There has been interest in its use both in diag-
nosis and potential for treatment with direct instilla-
tion of chemotherapy into the ducts49 (see Chapter 3).
Magnetic resonance imaging (MRI)
MRI can be used to image DCIS and is currently
being investigated in a number of trials. DCIS may
identify occult multifocal or contralateral disease,
but there are concerns about the potential of MRI
to overestimate the extent of disease, leading to
wider than necessary excisions, and unnecessary
mastectomy or identifying high numbers of contra-
lateral lesions that turn out to be benign. There are
also concerns that MRI might detect ­biologically
­insignificant disease that could increase ‘over-treat-
ment’. It therefore remains under investigation in
trials and has no routine role in assessing DCIS.
Treatment: mastectomy
versus breast-conserving
surgery
Even though there is current debate over the po-
tential over-treatment of some cases of DCIS, the
accepted current standard of management is at pres-
ent surgical.
Mastectomy
The long-term recurrence rate following mas-
tectomy for DCIS is less than 1%.50 As current
evidence (see p. 181) points to DCIS being predomi-
nantly unicentric in origin, it is now recognised
that mastectomy is over-treatment for the majority
of patients.50 In 1983 mastectomy was performed
for 71% of cases of DCIS in the USA but this had
dropped to 44% by 1992.51 Mastectomy is now re-
served for patients with larger areas of DCIS (arbi-
trarily considered as >4 cm), for multicentric disease
and for patients where radiotherapy is contraindi-
cated. Women should also be offered mastectomy if
the excision margins are involved following breast-
conserving surgery and the patient is not deemed
suitable for re-excision. Rates of re-excision versus
mastectomy vary widely in different units. Women
with DCIS requiring mastectomy are excellent can-
didates for skin-sparing mastectomy and immediate
breast reconstruction.
Breast-conserving surgery
Breast-conserving surgery is the treatment of
choice for small localised areas of DCIS (generally
those <4 cm in diameter). Larger areas of DCIS
can be excised but often require a reshaping or an
oncoplastic procedure combined with a contralat-
eral breast reduction to achieve symmetry. Areas
of DCIS usually need to be radiologically localised
preoperatively, as they are predominantly impal-
pable (see p. 181). Multiple wires may assist the
surgeon and thus increase the rates of complete
excision. The lesion should be excised in one piece

Treatment of ductal carcinoma in situ
185
if possible and ­orientated with radio opaque mark-
ers. Before wound closure, the specimen should
undergo radiography to ensure that all suspicious
microcalcifications have been removed and are
clear of the radial margins. Many surgeons use a
four-quadrant cavity biopsy, with or without India
ink, to assess the margins. The pathologist should
assess the histological margin status and document
this in the histology report. If the margins are close
(<1 mm), the patient should undergo cavity re-ex-
cision, as margin status is a key prognostic factor
for local recurrence.
The recommended treatment protocol for DCIS is
shown in Fig. 11.2.
Axillary staging
The incidence of macroscopic lymph node metasta-
sis in DCIS is less than 1% and should prompt thor-
ough pathological examination for occult invasion.
Formal axillary staging in women with DCIS should
not be performed alongside breast-conserving sur-
gery.52 However, National Institute for Health and
Clinical Excellence (NICE) guidelines recommend
that a sentinel lymph node biopsy should be per-
formed at the same time as mastectomy for DCIS52
and women should be counselled as to the indica-
tions for this. The rationale for performing sentinel
lymph node biopsy with mastectomy is the potential
DCIS on core biopsy
<4 cm/localised*
>4 cm† or multicentric*
Breast conserving
surgery
(Patient's choice
or radiotherapy
contraindicated)
± Reconstruction
Simple
mastectomy
Margins still
involved#
Margins involved
or <1 mm
Re-excise cavity
Re-excise cavity
Suspicious
microcalcifications
remain
Margins clear
>1 mm
<1.5 cm, non-high
grade, oestrogen
receptor positive
>1.5 cm, high grade
No
radiotherapy
Oestrogen receptor
negative
Consider
adjuvant
radiotherapy
No adjuvant
tamoxifen
Consider
tamoxifen
20 mg daily
for 5 years
Or offer patient enrolment
into clinical trials
Intraoperative X-ray
All suspicious
microcalcifications
excised
Histological
margin status
Oestrogen receptor
positive
Figure 11.2  •  Recommended treatment
algorithm for ductal carcinoma in situ
(DCIS). *Determined mammographically.
Shaded boxes indicate those treatments
suggested by the results of recent
trials.55,66 †Areas of DCIS >4 cm can be
treated by breast conservation if unifocal
and patient has large breasts, or is
suitable for an oncoplastic procedure.
#A further re-excision can be attempted
providing the final cosmetic result is
acceptable to the patient.

Chapter 11
186
of occult invasive disease that may be identified his-
tologically in a large area of DCIS. This would sub-
sequently require axillary staging. A sentinel lymph
node biopsy cannot easily be performed after a
mastectomy. Patients found to have positive lymph
nodes have occult invasive disease and should be
managed accordingly. A study by Veronesi et  al.
of 508 patients with pure DCIS found that nine
patients (1.8%) had epithelial cells found in the
sentinel node (five of these nine cases were micro-
metastases alone). None of the cases showed further
lymph node involvement at formal axillary dissec-
tion.53 A further study that looked retrospectively at
the NSABP B-17 and B-24 data, from patients who
had undergone local excision of DCIS with clear
margins (no axillary surgery at initial treatment),
showed that the ipsilateral nodal recurrence rate
was 0.83 per 1000 patient-years in the B-17 trial
and 0.36 per 1000 patient-years in the B-24 trial.
Meta-analysis of the published literature showed
approximately 1.8% of DCIS (almost entirely G3 or
high-grade disease) had involved sentinel nodes.54
Recurrence: rates and
predictors
No trial has specifically evaluated breast-conserving
surgery versus mastectomy in DCIS. The long-term
recurrence rate following mastectomy is known to
be very low at less than 1%.50 The majority of these
recurrences are invasive disease. This reflects the
fact that after mastectomy no imaging is performed
routinely of the ipsilateral side and further disease is
only detected when it becomes clinically apparent –
at which stage it is most likely to be invasive. The
recurrence rate for breast-conserving surgery alone
has been reported to be up to 25% at 8 years follow-
up, with up to 50% of recurrences (i.e. 12.5% of all
cases) being invasive disease.13,48,55 The remaining
50% of recurrences are in situ tumours.56 Reviews
of clinical and pathological variables have demon-
strated certain unfavourable tumour characteristics
and these are outlined below. Recurrence rates have
fallen significantly over time.
Assessment of excision margins
A fundamental risk factor for recurrence is inade-
quate excision following breast-conserving surgery.
This is judged as close (<1 mm) or involved margins48
and/or failure to remove all suspicious microcalcifi-
cations.57 Excision margin width has three times the
power of tumour grade in predicting local recur-
rence.58 The NSABP-B17, NSABP-B24 and EORTC
clinical trials all revealed that the presence of clear
margins after local excision significantly decreased
tumour recurrence.13,59–61 On multivariate analysis
of the EORTC trial, non-specified, close or involved
margins conferred a hazard ratio of 2.07 (95% con-
fidence interval (CI) 1.35–3.16, P = 0.0008) com-
pared with clear margins.61 The NSABP-B24 trial
found a covariate relative risk of 1.68 (95% CI
1.20–2.34) if the margins were involved.59 No pro-
spective trials have looked at the optimum excision
width required for in situ or invasive cancer. When
considering the extent of surgical excision there has
to be balance between minimising recurrence and
producing an acceptable cosmetic outcome. A retro-
spective study by Chan et al.48 reported that women
with clear margins (judged as greater than 1 mm)
had an 8.1% recurrence at a median follow-up of
47 months compared with 37.9% recurrence where
excision margins were close (1 mm). There was no
improvement in recurrence rates in more widely ex-
cised lesions. The recent meta-analysis performed
by Wang et  al.62 suggested a 10-mm margin was
superior to lesser margins for local recurrence but
this conflicts with an earlier meta-analysis, which
suggested 2 mm.63 Part of the problem of defining
an optimum margin is that these analyses are af-
fected by confounding factors. The 10- and 2-mm
distances also rely on a small proportion of patients
treated in very few centres. At present, as Morrow
and Katz conclude, there is no compelling evidence
that bigger is better for margins in DCIS.64
High-grade/comedo tumours
High-grade tumours and tumours showing comedo
necrosis are independent risk factors for recurrence.
In a review of the EORTC 10853 trial,61 high nuclear
grade had a hazard ratio of 2.23 (95% CI 1.41–3.51,
P = 0.0011) for local recurrence, with 22% of high-
grade tumours and 11% of intermediate-grade tu-
mours developing either recurrent DCIS or invasive
tumour. Comedo necrosis was also shown to be re-
lated to local recurrence, 18% of patients with DCIS
having comedo necrosis developing recurrence (haz-
ard ratio 1.80, 95% CI 1.08–3.00, P = 0.0183).

Treatment of ductal carcinoma in situ
187
Histological type and tumour
architecture
The degree of tumour differentiation is predictive
of both local recurrence and metastatic disease. In
the EORTC trial,13,61 poorly differentiated tumours
were at significantly higher risk of developing DCIS
recurrence (hazard ratio 3.58, 95% CI 1.68–7.62,
P  =  0.0001) and metastasis (hazard ratio 6.65,
95% CI 1.46–30.22, P = 0.00083) compared with
well-differentiated tumours. In this same trial, his-
tological type was also strongly related to DCIS re-
currence, though not to invasive recurrence. Both
solid/comedo DCIS (hazard ratio 4.40, 95% CI
2.28–8.48, P = 0.0001) and cribriform DCIS (haz-
ard ratio 3.74, 95% CI 1.91–7.30, P  =  0.0001)
were found to be much more likely to recur than
clinging or micropapillary tumours. Within the
well-­differentiated group, no tumours with cling-
ing DCIS recurred.61 It has been suggested that this
well-differentiated clinging DCIS should be reclassi-
fied separately as ‘columnar alteration with promi-
nent apical snouts and secretion’,65 with debate
as to whether this subtype should be managed as
atypical ductal hyperplasia or LCIS.
Age at diagnosis
A further risk factor for recurrence irrespective of
tumour grade or type is young age (<40 years) at
diagnosis. The EORTC 10853 trial13,61 found that
women less than 40 years at diagnosis were more
likely to recur (hazard ratio 2.54, 95% CI 1.53–
4.23, P  =  0.010) than older women. The NSABP
B-24 trial59 found that the rate of ipsilateral breast
tumours (in the placebo population) in women aged
49  years or less at diagnosis was 33.3 per 1000,
compared with 13.0 for those aged 50 and above.
In the UK/ANZ DCIS trial,66,67 only a small propor-
tion (9.5%) of women was less than 50 years old at
diagnosis. The power of this study is thus limited,
but of these younger women, 26% recurred after
excision and tamoxifen compared with only 17% of
women older than 50 years. Rodrigues et al.68 stud-
ied women aged 42 years or less (mean age 38.5)
or women aged 60 years or more (mean age 67.8)
at diagnosis. They found that although there was
no difference in tumour grade, comedo necrosis or
overall histology (also found in the EORTC trial)
between the groups, compared with older patients
HER-2 was more frequently overexpressed in the
younger patient population. Approximately 65% of
the younger age group were HER-2 positive com-
pared with 38% of the older age group (P = 0.06).
No significant difference was found between oes-
trogen receptor, progesterone receptor, p53, Ki67,
cyclin D1 or bcl-2 expression.
Tumour size and palpability
None of the major trials have found any statisti-
cal significance between recurrence and size. The
NSABP-B17 trial55 found that the size of mammo-
graphically detected tumours was not significant in
predicting ipsilateral recurrence. However, when
researchers examined clustering of microcalcifica-
tions in women whose mammograms did not show
a tumour mass, they found that clustered microcal-
cifications greater than 10 mm (relative risk 2.06,
95% CI 1.36–3.10) or scattered calcifications (rela-
tive risk 2.41, 95% CI 1.40–4.16) had a signifi-
cantly higher ipsilateral recurrence than clustered
calcifications of 10 mm or less. The problem is that
there may be differences in histology between the
groups, so counfounding the analysis of size. The
EORTC 10853 trial61 found no difference in recur-
rence rates between tumours less than 10 mm in size
and those 10–20 mm or greater than 20 mm in size
(P = 0.2127). However, tumours that were clinically
apparent rather than mammographically detected
were more likely to recur (covariate relative risk
2.17, 95% CI 1.53–3.08).61
Scoring systems
In order to bring together the most clinically rel-
evant risk factors, Silverstein and Lagois69 devel-
oped the Van Nuys Prognostic Index, with the
aim of predicting which women would be at risk
of recurrence following breast-conserving sur-
gery. This numerical algorithm was derived from
regression analysis of retrospective data pooled
from patients with DCIS treated at two centres in
the USA. Recurrence is clearly multifactorial but
the problem with the Van Nuys Index is that the
data derived were not randomised and used his-
torical controls. The formula encompassed tumour
size, margin width and pathological classification.

Chapter 11
188
The index has since been ­modified as the University
of Southern California/Van Nuys Prognostic Index
(USC/VNPI) and now includes patient age.69 Each
criterion is weighted and scored 1, 2 or 3 and the
individual scores combined to give an overall score
from 4 to 12. Scores of 4–6, 7–9 and 10–12 are
said to be at low, moderate and high risk of 5-year
recurrence, respectively. It was designed to achieve
a less than 20% recurrence rate at 12 years. The
data are skewed by the fact that 80% of large tu-
mours (>4 cm) recurred, whereas in the UK these
women would have undergone mastectomy. These
large tumours were also more likely high grade
and incompletely excised. The value of the scoring
system for a UK population, where the majority of
cases of DCIS are small (<2 cm) and screen detected
(patients usually over 50  years old), may be lim-
ited. For instance, Boland et al.58 were unable to
demonstrate that size was a marker of recurrence
in screen-detected DCIS in the UK.
Markers of recurrence
There has also been interest in another member of
the type 1 tyrosine kinase receptor family, HER-4.
DCIS and invasive tumours that show co-expression
of HER-2 and HER-4 have a better prognosis (re-
duced recurrence) than HER-2-positive, HER-
4-negative tumours.71–72 A summary of the risk
factors for DCIS recurrence is shown in Table 11.2
(see Lari SA and Kuerer HM73 review of DCIS bio-
logical prognostic markers).
The use of genomics looks as if it may have the po-
tential to identify patients and high and low risk of re-
currence. Oncotype DX marketed by Genomic Health
is a scoring system for invasive cancer recurrence
based on a 21-gene assay, Researchers have recently
shown that the use of a modified 12-gene DCIS as-
say (Oncotype DX DCIS) using data from the Eastern
Cooperative Oncology Group study 5194 trial (see
later) can identify 75% of women from this cohort
with low- and intermediate-grade DCIS who have a
low risk of recurrence after treatment for DCIS (and
could therefore avoid radiotherapy).
Adjuvant therapy
Radiotherapy
Four main trials and a subsequent Cochrane re-
view74 have examined the value of radiotherapy
following breast-conserving surgery for DCIS. The
NSABP-B17,55 EORTC 10853,13 UK/ANZ DCIS66,67
and SWEDCIS75 trials each studied a radiation dose
of 50 Gy in 25 fractions. All found a significant
reduction in ipsilateral recurrence following radio-
therapy. However, none of the trials have shown any
impact on mortality (Table 11.3, Fig. 11.3).
The reduction in recurrence was similar for both
in situ and invasive disease. In the EORTC trial,
To improve the detection of specific patient
groups at increased risk of recurrence, biological
markers that might help determine recurrence
potential in DCIS are being investigated.
Provenzano et al.70 found that oestrogen receptor,
progesterone receptor and bcl-2 negativity and
HER-2 and p21 positivity were associated with
an increased risk of clinical recurrence. This was
irrespective of tumour grade. Oestrogen receptor,
progesterone receptor, bcl-2 and HER-2 were
found to be interdependent of each other, whereas
p21 was found to be independent of the above
associations, and is thought to reflect the differing
biological pathways of action between the markers.
Excision margins
Margins <1 mm after breast-
conserving surgery
Tumour grade
High grade (III)
Comedo necrosis
Present
Histological type
Poorly differentiated
Patient age
Younger age at diagnosis
(<40 years)
Biological markers

Negativity
Oestrogen receptor

Progesterone receptor

bcl-2

HER-4
Positivity
HER-2

p21

p53

Ki67 (high-percentage
expression)
Patient presentation
Symptomatic
Tumour size
Not significant
Table 11.2  •  Risk factors for recurrence of ductal
carcinoma in situ
Poor-prognosis tumours often possess multiple bad prognostic
features, i.e. they tend to be poorly differentiated high-grade,
comedo tumours that are oestrogen receptor negative and
overexpress c-erbB-2.

Treatment of ductal carcinoma in situ
189

NSABP-17*
NSABP-24*
EORTC 10853†
UK/ANZ DCIS‡

BCS
alone

BCS and
XRT

BCS and
XRT
BCS,
XRT and
tamoxifen

BCS
alone
BCS
and
XRT

BCS
alone

BCS
and XRT

BCS and
tamoxifen
BCS,
XRT and
tamoxifen
Number of patients
403
411
899
899
500
502
544
267
567
316
Number of local recurrences at median follow-up:
43 months
64
28
–
–
–
–
–
–
–
–
48 months
–
–
–
–
83
53
–
–
–
–
53 months
–
–
–
–
–
–
119
22
101
21
74 months
–
–
130
84
–
–
–
–
–
–
90 months
140
47
–
–
–
–
–
–
–
–
126 months
–
–
–
–
132
75
–
–
–
–
152 months
–
–
–
–
–
–
174
35
135
32
Local recurrence rates:
4-year all recurrences
–
–
–
–
16%
9%
–
–
–
–
4-year invasive
–
–
–
–
8%
4%
–
–
–
–
5-year all recurrences
–
–
13%
8.2%
–
–
15%
3%
12%
3%
5-year invasive
–
–
7%
4.1%
–
–
5%
1%
5%
2%
8-year all recurrences
27%
12%
–
–
–
–
–
–
–
–
8-year invasive
13%
4%
–
–
–
–
–
–
–
–
10-year all recurrences
–
–
–
–
26%
15%
–
–
–
–
10-year invasive
–
–
–
–
13%
8%
–
–
–
–
Annual recurrence rate
–
–
–
–
–
–
3.2%
1.2%
2.2%
0.9%
Number of distant metastases
6
9
7
3
20
23
–
–
–
–
Total number of contralateral breast events
19
20
36
18
28
39
29
7
11
9
Number of contralateral invasive breast cancers
16
12
23
15
19
28
20
5
7
7
Table 11.3  •  Summary of major radiotherapy/tamoxifen clinical trials following breast-conserving therapy for ductal carcinoma in situ
(Continued )

Chapter 11
190

NSABP-17*
NSABP-24*
EORTC 10853†
UK/ANZ DCIS‡

BCS
alone

BCS and
XRT

BCS and
XRT
BCS,
XRT and
tamoxifen

BCS
alone
BCS
and
XRT

BCS
alone

BCS
and XRT

BCS and
tamoxifen
BCS,
XRT and
tamoxifen
Bilateral event-free survival at:
4 years
–
–
–
–
82%
86%
–
–
–
–
5 years
74%
84%
83%
87%
–
–
85%
97%
88%
97%
8 years
60%
75%
–
–
–
–
–
–
–
–
10 years
–
–
–
–
74%
85%
–
–
–
–
BCS, breast-conserving surgery; XRT, radiotherapy.
*Fisher ER, Dignam J, Tan-Chiu E et al. Pathologic findings from the National Surgical Adjuvant Breast Project (NSABP) eight-year update of Protocol B-17: intraductal carcinoma. Cancer 1999;
86:429–38.
†Julien J, Bijker N, Fentimen I et al. Radiotherapy in breast-conserving treatment for ductal carcinoma in situ: first results of the EORTC randomized phase III trial 10853. EORTC Breast Cancer
Cooperative Group and EORTC Radiotherapy group. Lancet 2000; 355:528–33. Bijker N, Meijnen P. Peterse JL et al. Breast-conserving treatment with or without radiotherapy in ductal carcinoma-
in-situ: ten-year results of European Organisation for Research and Treatment of Cancer randomized phase III trial 10853 – a study by the EORTC Breast Cancer Cooperative Group and EORTC
Radiotherapy Group. J Clin Oncol 2006; 24(21):3381–7.
‡UK Coordinating Committee on Cancer Research (UKCCCR). Ductal carcinoma in situ (DCIS) Working Party on behalf of DCIS trialists in the UK, Australia and New Zealand, Radiotherapy and
tamoxifen in women with completely excised ductal carcinoma in situ of the breast in the UK, Australia and New Zealand: randomised controlled trial. Lancet 2003; 362:95–103. Cuzick J, Sestaka I,
Pinder S, et al Effect of tamoxifen and radiotherapy in women with locally excised ductal carcinoma in situ: long-term results from the UK/ANZ DCIS trial. Lancet Oncol. 2010; 12(1): 21–9.
Table 11.3  •  (cont.) Summary of major radiotherapy/tamoxifen clinical trials following breast-conserving therapy for ductal carcinoma in situ

Treatment of ductal carcinoma in situ
191
radiotherapy reduced the risk of DCIS recurrence
by 48% (P = 0.0011) and invasive local recurrence
by 42% (P = 0.0065) at a median of 10.7 years'
follow-up.76 The UK DCIS trial found that after a
median follow-up of 12.5 years there was a reduced
incidence of ipsilateral invasive disease (0.32, 0.19–
0.56; P < 0.0001) and ipsilateral DCIS (0.38, 0.22–
0.63; P < 0.0001).67 Both groups had similar low
risks of metastases and death. No survival advan-
tage following radiotherapy was found in any trial.
The Cochrane review concluded that ‘nine women
require treatment with radiotherapy to prevent one
ipsilateral recurrence’.74
Two studies have looked at avoiding radiother-
apy in ‘low-risk’ cases of pure DCIS; one by Wong
et  al.77 was stopped in line with the trial protocol
because of high recurrence rates, although most re-
currences were mammographically detected DCIS
and the remainder node-negative invasive cancers
and thus did not impact overall survival. They
concluded that it remained unclear how to iden-
tify patients who had a low recurrence risk with
excision alone, and that despite margins >1 cm
(or having had re-excision) the local recurrence rate
was still high. The second, the Eastern Cooperative
Oncology Group study 5194 (the study in which
the Oncotype DX DCIS score was validated (see previ-
ously)),78 included 558 cases of low- or intermediate-
grade DCIS, which measured 2.5 cm or less, and 103
cases of high-grade DCIS of 1 cm or smaller which
had been excised completely with 3-mm margins,
none of which had radiation therapy but they may
have had tamoxifen. The 5-year ipsilateral overall
breast event rate for low/intermediate-grade DCIS
was 6.1% (3% for invasive disease alone). For the
high-grade lesions this was increased to 15.3%
(7.5% for invasive disease). They concluded that a
6% 5-year ipsilateral breast event rate for low/inter-
mediate-grade tumours may be acceptable to patients
and physicians, but that the 15% high-grade event
rate would not be. They suggested that specimens
need to be rigorously evaluated to ensure they are
actually ‘low risk’. This study included patients with
DCIS with a median size of 1 cm. Seventy-five per
cent of the patients were classified by the Oncotype
DX assay as low risk, 14% intermediate risk and
11% high risk. Low-risk patients had a 10-year event
rate of 12% and a 5% rate of developing an invasive
cancer with no radiotherapy. This event rate is higher
than one currently sees in invasive cancer after breast
conservation surgery and radiotherapy but many of
these events will be further DCIS which can be treated
effectively by further surgery +/- radiotherapy.
Endocrine therapy
Although radiotherapy reduces tumour recur-
rence following breast-conserving surgery, there is
B-17
EORTC
UK/ANZ
Combined
0.4 0.48 0.6
0.8
1
1.2
Odds ratio
Figure 11.3  •  Radiotherapy trials overview: ipsilateral
ductal carcinoma in situ (DCIS) and invasive recurrences.
This Forrest plot of the major randomised controlled trials
of radiotherapy in DCIS (B17,55 EORTC13 and UK/ANZ66)
shows a significant reduction in ipsilateral recurrence risk
following radiotherapy for all trials, with a combined odds
ratio for the reduction in recurrence of DCIS and invasive
disease of 0.48 for all trials. Reproduced from Cuzick J.
Treatment of DCIS – results from clinical trials. Surg Oncol
2003; 12:213–9. With permission from Elsevier.
Current NICE guidelines recommend that you
should: ‘Offer adjuvant radiotherapy to patients with
DCIS following adequate breast-conserving surgery
and discuss with them the potential benefits and
risks.’52
The National Institutes for Health State-of-the-
Science conference included a multiprofessional
event of independent panels of health professionals
and public representatives. This reviewed systematic
literature on DCIS, with presentations by investigators
working in wide-ranging areas of DCIS management
(2009).79 It concluded that for radiotherapy:
‘Randomised clinical trials demonstrate that all
subsets of patients benefit from radiotherapy in
terms of decreased local recurrence. However,
there may be a subgroup of women who have
DCIS in which the risk of local recurrence is so
low that radiotherapy may be of no benefit. In
addition, there also may be a subset of women
who can be monitored after biopsy in lieu of
surgery or other therapies.’