Journal of Cancer Therapy, 2012, 3, 655-661
http://dx.doi.org/10.4236/jct.2012.325085 Published Online October 2012 (http://www.SciRP.org/journal/jct)
655
Mammographic Findings Associated with Accelerated
Partial Breast Irradiation Using Single Fraction
Intraoperative Radiotherapy
Kathleen C. Horst1, Debra M. Ikeda2, Katherine E. Fero1, Jafi A. Lipson2, Sunita Pal2,
Don R. Goffinet1, Frederick M. Dirbas3
1Departments of Radiation Oncology, Stanford University, Stanford, USA; 2Departments of Diagnostic Radiology, Stanford Univer-
sity, Stanford, USA; 3Departments of Surgery, Stanford University, Stanford, USA.
Received June 15th, 2012; revised July 18th, 2012; accepted July 29th, 2012
ABSTRACT
Purpose: To evaluate the mammographic findings of women treated with accelerated partial breast irradiation (APBI)
using single-fraction intraoperative radiotherapy (IORT). Materials/Methods: Women ≥ 40 years of age with unifocal
invasive or intraductal carcinoma ≤ 2.5 cm on physical examination, mammography, and ultrasound were enrolled on
an APBI trial using single fraction IORT. Post-treatment mammographic imaging was obtained at 6 months, 1 year, and
then annually. Results: Between 12/02 and 6/04, 17 women underwent IORT at the time of lumpectomy (median age =
60 years; range = 40 - 83). The initial post-IORT mammogram showed increased density at the lumpectomy site in 11
patients (65%), while six patients (35%) had architectural distortion in the area of the irradiated tissue. Fifteen patients
(88%) had numerous punctate, benign-appearing calcifications corresponding to the irradiated region. There was focal
skin thickening near the incision in 13 patients (76%). At a median of 67 months, architectural distortion had stabilized
and the benign-appearing calcifications remained stable in number and character. Eight patients (47%) had mammo-
graphic findings consistent with fat necrosis, ranging in size from 0.5 - 4 cm. Conclusions: After lumpectomy and
IORT, mammographic changes include increased density and benign appearing calcifications in the irradiated region
with focal skin thickening. These changes appear to stabilize over time and are consistent with post-treatment changes.
These changes are important to identify in order to characterize benign changes from recurrent tumor.
Keywords: Accelerated Partial Breast Irradiation (APBI); Intraoperative Radiotherapy (IORT); Breast Cancer;
Mammography; Microcalcifications; Fat Necrosis
1. Introduction
Multiple prospective, randomized trials have demon-
strated that whole-breast irradiation (WBI) reduces the
risk of ipsilateral breast tumor recurrence (IBTR) after
breast conserving surgery (BCS) [1-6]. Given these long-
term results, the combination of BCS and WBI has been
considered a standard treatment option for women with
early stage breast cancer [7].
More recently, accelerated partial breast irradiation
(APBI) has emerged as an alternative to WBI [8]. APBI
targets the lumpectomy cavity plus a margin of normal
breast tissue and allows for treatment to be delivered in
1 - 5 days compared to the standard 6 - 7 weeks with
WBI. Phase III trials comparing WBI versus APBI are
ongoing in Canada, Europe, and the United States. Vari-
ous techniques are being utilized, including interstitial or
intracavitary brachytherapy, 3D conformal radiotherapy
(3D-CRT), and single fraction intraoperative radiother-
apy (IORT) [9-12]. A recently published phase III trial
evaluating IORT using the Intrabeam® device demon-
strated equivalent recurrence rates and toxicity compared
to WBI [13].
The increasing use of APBI raises questions regarding
the early and long-term safety of the higher radiation
doses per fraction [14]. In addition to toxicity, there are
concerns about alterations in mammographic findings
that may hinder the ability to detect recurrences [15,16].
It is therefore important to characterize mammographic
changes after APBI in order to limit fals positive findings
that could lead to unnecessary biopsies.
At our institution, single-fraction IORT has been of-
fered to women with early stage breast cancer. Data from
European centers has suggested the approach is safe and
effective [13,17]. However, the single, large radiotherapy
dose delivered with IORT has raised concerns for some

Mammographic Findings Associated with Accelerated Partial Breast Irradiation Using Single Fraction
Intraoperative Radiotherapy
656
that it may be associated with even greater sequelae
compared with other forms of APBI [18]. The aim of our
study was to describe the mammographic findings of
women treated with APBI using single-fraction IORT.
2. Methods
2.1. Patient Selection
Between December 2002-June 2004, women with Stage
0/I breast cancer were evaluated for an IRB-approved
clinical trial with APBI. Inclusion criteria included age ≥
40 with unifocal invasive ductal carcinoma (IDC) or
ductal carcinoma in-situ (DCIS) measuring ≤ 2.5 cm on
clinical or radiographic assessment. Exclusion criteria
included IDC associated with an extensive intraductal
component (EIC), invasive lobular carcinoma, tumor ap-
proximating or involving skin and/or pectoralis fascia, or
involved axillary nodes. All patients underwent pre-op-
erative mammography with ultrasound if clinically ap-
propriate. Treatment options were presented to patients,
including mastectomy, BCS with standard WBI, or APBI
with IORT at the time of BCS. Patients underwent pre-
operative, contrast-enhanced breast magnetic resonance
imaging (MRI) to confirm unifocal disease. Abnormal
MRI findings were evaluated by US- or MRI-guided bi-
opsy. Written informed consent was obtained from all
patients prior to IORT by both the surgical and radiation
oncology teams.
2.2. Surgery and Intraoperative Radiotherapy
Sentinel lymph node (SLN) biopsy, if indicated, was
performed first followed by touch preparation or frozen
section of excised SLN(s). SLN involvement precluded
the use of IORT per protocol.
After excision of the lesion, specimen radiography was
obtained to confirm excision with tumor-free margins.
The breast tissue surrounding the cavity was then cir-
cumferentially freed from the skin anteriorly and from
the pectoralis major muscle posteriorly for a distance of
5 - 10 cm from the edge of the cavity as described by
Veronesi et al. [17,19]. A 3 mm lead plate was placed
upon the pectoralis major muscle to limit the chest wall
from exit radiation dose. The mobilized lumpectomy
cavity margins were temporarily approximated to each
other with Prolene sutures (Johnson and Johnson/Ethicon,
Somerville, N.J.) over the lead plate. The target volume
for irradiation was defined to include 1 - 3 cm of the
lumpectomy cavity margins circumferentially.
A self-retaining retractor (Lone Star Medical Products,
Inc. Stafford, TX) was used to retract skin and a 5 - 7.5
cm diameter collimator was placed directly over the tar-
get volume. The collimator was then mounted to a Phil-
lips 250 RT orthovoltage radiation unit. Seventeen Gy
(surface dose) was delivered to the target volume in a
single fraction over the course of 15 - 20 minutes. At the
completion of radiotherapy, the collimator and lead plate
were removed, and the incision was closed over a small
closed-suction drain (Jackson-Pratt®, Cardinal Health,
Inc, Dublin, Ohio) that remained in place for 3 - 10 days
to minimize seroma formation. All patients received
prophylactic antibiotics until drain removal.ase do not
revise any of the current designations.
2.3. Follow-Up Evaluation and Post-Operative
Imaging
Per protocol, treated patients were seen after surgery at 1
week, 1 month, 3 months, every 3 months for 2 years,
then every 6 months.
If final pathology deemed margins < 2 mm, the rec-
ommendation was to proceed with re-excision lumpec-
tomy followed by WBI. Women who were found to have
lymph node involvement on final pathology were advised
to undergo completion axillary lymph node dissection
(per standard recommendations at that time) as well as
WBI. Adjuvant systemic therapy was left to the discre-
tion of the medical oncologists.
Skin changes identified on physical examination, com-
plications, and disease status were documented at each
follow up visit. Fine needle aspiration (FNA), core nee-
dle biopsy, or excisional biopsy was performed for any
clinical or radiologic abnormalities suspicious for recur-
rence or a new primary.
Patients underwent unilateral diagnostic mammogra-
phy of the treated breast six months after lumpectomy
and IORT. Bilateral mammograms were performed at
one year, and then annually. Additional images were ob-
tained as determined by our breast imagers. Three radi-
ologists (DI, JA, SP) retrospectively reviewed and re-
corded mammographic findings, including breast tissue
density, the presence or absence of masses or microcalci-
fications, and changes in the skin and irradiated tissue.
3. Results
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Mammographic Findings Associated with Accelerated Partial Breast Irradiation Using Single Fraction
Intraoperative Radiotherapy
657
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3.1. Pre-Treatment Lesion Characteristics and
Final Tumor Pathology
During the study period 17 patients underwent IORT at
the time of lumpectomy (n = 11) or re-excision lumpec-
tomy (n = 6) (median age = 60 years; range = 40 - 83).
At initial presentation, 14 patients (82%) had lesions that
were non-palpable while 3 (18%) had palpable tumors.
Pre-operative mammography demonstrated 16 of the 17
lesions (94%), characterized as masses having irregular
or spiculated margins with (n = 1) or without microcalci-
fications (n = 13), or pleomorphic microcalcifications
without an associated mass (n = 2). Fourteen patients
underwent breast ultrasound for further characterization
of palpable findings (n = 3) or for abnormalities seen on
mammography (n = 11). Pre-operative breast MRI in all
17 patients confirmed unifocal disease.
Eleven of the 17 patients (65%) underwent primary
lumpectomy and 6 (35%) re-excision lumpectomy at the
time of IORT. Fourteen of the 17 tumors (82%) were
IDC, 12 of which had associated DCIS. Three patients
had DCIS. The median tumor size on final pathology was
13 mm (range = 1 - 24 mm).
3.2. Post-Treatment Follow up and Imaging
At a median follow-up of 95 months (range = 86 - 104
months), one patient had a local recurrence. While all
patients were free of breast cancer distant metastasis, one
patient died of colon cancer. All 17 patients had their first
post-treatment mammogram 4 - 6 months after IORT. On
the initial post-IORT mammogram, the lumpectomy/
IORT site showed increased density, as compared to the
pre-treatment mammogram, in 11 patients (65%), with 8
having density changes in a cylindrical-shaped pattern
extending from the skin toward the chest wall corre-
sponding to the target volume irradiated (Figure 1).
The remaining six patients (35%) had architectural
distortion in the area of the irradiated tissue. There was
little edematous change in the breast tissue at the lum-
pectomy site.
Fifteen patients (88%) had numerous scattered, punc-
tate, benign-appearing calcifications that corresponded to
the irradiated region and extended along the chest wall
(Figure 2).
Some of these were fine, round calcifications while
others were more coarse and dense. Despite the lack of
skin irradiation, 13 patients (76%) showed skin thicken-
ing near the skin incision, consistent with post-surgical
healing. Skin away from the biopsy site was of normal
thickness.
Long-term mammographic imaging was available for
(a)
(b)
Figure 1. Unilateral mammogram 16 months post IORT in
a 58 year old woman with high grade DCIS. (a) MLO view
with focal cylindrical density extending from the scar to the
chest wall. This density corresponds to the irradiated tissue;
(b) CC view again demonstrating the asymmetric changes
in the medial breast extending from the skin to the chest
wall, the area treated with the single fraction intra-opera-
tive radiation.
15 patients at a median of 67 months (range 19 - 101)
from the IORT treatment. In the 8 patients with cylindri-
cal densities corresponding to the irradiated region, the
area of increased density continued to decrease over time
(Figure 3).
Architectural distortion was noted in all 15 patients
and had stabilized over time. All patients had benign-
appearing microcalcifications that remained stable in
number and character with longer follow up. No patient
had a suspicious cluster of calcifications warranting bi-
opsy. Focal skin thickening also persisted in a stable

Mammographic Findings Associated with Accelerated Partial Breast Irradiation Using Single Fraction
Intraoperative Radiotherapy
658
(a)
(b)
Figure 2. Magnification CC (a) and Lateral (b) mammo-
gram in a woman treated 16 months earlier with IORT
demonstrates numerous round, smooth, small calcifications
(arrows) throughout most of the density that conforms to
the single fraction intra-operative irradiated tissue and
along the chest wall.
fashion.
Eight patients (47%) had mammographic findings con-
sistent with fat necrosis, zranging in size from 0.5 - 4 cm.
In patients who did not develop fat necrosis, most had
heterogeneously dense breast tissue, while those who did
(a)
(b)
Figure 3. Magnification views at 10 months post-IORT
treatment (a) and 16 months post-IORT (b). Focused den-
sity decreased over time while the calcifications remained
the same.
develop fat necrosis mostly had scattered fibroglandular
breast tissue.
4. Discussion
Breast conservation therapy alters the mammographic
appearance of the treated breast. In one of the earliest
papers discussing microcalcifications after BCS and WBI,
Libshitz et al. characterized microcalcifications in the
irradiated tissue in comparison to microcalcifications that
indicated recurrent cancer [20]. Orel et al. further noted

Mammographic Findings Associated with Accelerated Partial Breast Irradiation Using Single Fraction
Intraoperative Radiotherapy
659
that benign calcifications in the irradiated field pro-
gressed over time from fine microcalcifications to dys-
trophic calcifications [21]. Dershaw et al. also described
new faint, punctate calcifications that were clearly dis-
similar from calcifications associated with breast carci-
noma, which are usually irregular, branching, and/or
pleomorphic in appearance [22]. These earlier descrip-
tions of mammographic changes after WBI were impor-
tant in defining post-treatment changes, such as skin
thickening, increased tissue density, architectural distor-
tion, increased trabecular thickening, edema, and/or mi-
crocalcifications, in contrast to changes associated with
in-breast tumor recurrences (IBTR). After BCS and WBI,
edema and increased tissue density typically resolve as
the acute inflammation gives way to fibrosis and scarring,
which are chronic tissue changes that occur as a result of
radiation damage to the microvasculature. Microcalcifi-
cations typically form later and range from punctate cal-
cifications to more coarse calcifications that have either
radiolucent centers or a lipid cyst with curvilinear mi-
crocalcifications at its margin.
Mammographic changes after APBI using IORT, how-
ever, tend to be more focal in nature and differ in time
course. In our patients, we found that skin thickening was
localized to the surgical incision and was noted at the
first 6-month post-treatment mammogram. The increased
tissue density conformed to the focal area of irradiated
tissue, developed early, and decreased over time. We did
not identify significant fibrosis in these patients, even
with long-term follow up. Benign calcifications appeared
in 88% of our patients at the first mammogram and re-
mained stable in number and appearance over time. Cal-
cifications consistent with fat necrosis developed in 47%,
and were more common in patients with lower breast
density.
Our findings are consistent with those reported in the
literature. Series investigating IORT as a boost or as sole
radiation treatment with either intraoperative electrons or
low energy X-rays have reported similar post-treatment
mammographic findings. Della Sala et al. and Carvalho
et al. reported early changes after IORT using electrons
that consisted of cutaneous thickening, architectural dis-
tortion, and benign calcifications which developed as
early as 6 - 12 months after treatment and remained sta-
ble or even increased up to 24 months [23,24]. Wasser et
al. found distinct, focal mammographic changes that ap-
peared to remain stable with long-term follow up after
IORT using 50 kV with or without WBI [25]. Consistent
with our findings, Kuzmiak et al. also found that mam-
mographic changes varied according to breast density,
with surgical scarring less apparent in those with lower
breast density [26].
These distinct mammographic changes appear to be
similar regardless of the APBI technique utilized. Lawenda
et al. identified architectural distortion and calcifications
in a series of patients treated on a dose escalation study
using low-dose-rate interstitial brachytherapy with 192 Ir.
The likelihood of having mammographic changes in-
creased with dose escalation, with 36.8%, 40%, and 50%
having focal mammographic findings in those treated
with 50, 55, and 60 Gy, respectively [27]. Esserman et al.
reported imaging findings in patients treated with APBI
using interstitial or intracavitary brachytherapy [28]. Forty-
one of 43 patients (95%) had focal increased density, and
8 patients (19%) had calcifications typical for fat necro-
sis appearing at 12 months of follow up. Ahmed et al.
reported focal findings consisting of fat necrosis, seroma
formation, and architectural distortion in patients treated
with MammoSite balloon brachytherapy which peaked at
21 months of follow up [29].
The findings with interstitial or intracavitary brachy-
therapy, which often delivers high or low-dose radio-
therapy to the lumpectomy cavity twice daily over 4 - 5
days, suggest that radiographic evidence of fat necrosis
may vary from approximately 3% to up to 19% - 20%
[27-30]. With single fraction IORT, the radiographic
description of fat necrosis is higher, ranging from 20% -
57% supporting the concern that breast tissue damage is,
indeed, likely related to the dose delivered per fraction
[23,24,31]. Interestingly, the appearance of microcalcifi-
cations in our cohort occurred earlier and more fre-
quently than what is typically seen with standard frac-
tionated breast radiotherapy. However, they remained
stable in number, size, and character with long-term
follow up. In contrast, patients who were treated with
APBI using high-dose-rate brachytherapy appear to have
a lower rate of post-treatment microcalcifications ini-
tially, but these seem to increase over time [32]. Inter-
estingly, most of these radiographic changes consistent
with fat necrosis continue to be asymptomatic. Longer
follow-up will be necessary to determine how these find-
ings evolve.
This study is limited by its retrospective nature, the
small sample size, and the fact that the breast radiologists
were not blinded. Our results therefore need to be con-
firmed in a larger series of patients treated with APBI
using IORT. The recently reported TARGIT trial (ref),
reported equivalent results of IORT compared to WBI
after BCS, however, no post-treatment imaging data are
available at this time [13].
Our findings confirm that mammographic changes af-
ter IORT, such as increased tissue density, architectural
distortion, and benign-appearing calcifications, appear
early in the irradiated tissue yet tend to decrease or re-
main stable over time. These findings can help guide

Mammographic Findings Associated with Accelerated Partial Breast Irradiation Using Single Fraction
Intraoperative Radiotherapy
660
physicians in radiographic follow up of patients treated
with APBI.
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