Pediatr Blood Cancer 2010;55:1306–1309
Breast Metastases in Children and Adolescents with Rhabdomyosarcoma:
Experience of the Italian Soft Tissue Sarcoma Committee
Paolo D’Angelo, MD,1,* Modesto Carli, MD,2Andrea Ferrari, MD,3Carla Manzitti, MD,4Rossella Mura, MD,5
Lucia Miglionico, MD,6Andrea Di Cataldo, MD,7Antonella Grigoli, MD,1Giovanni Cecchetto, MD,8and
Gianni Bisogno, MD2for the AIEOP Soft Tissue Sarcoma Committee
Background. Breast metastasis from rhabdomyosarcoma (RMS) is
an uncommon event but may be problematic in treatment decision-
making. Aim of the study was to evaluate clinical characteristics,
treatment, and subsequent outcome, of patients with RMS metasta-
sis in the breast, enrolled in four consecutive Associazione Italiana
di Ematologia ed Oncologia Pediatrica (AIEOP) Soft Tissue Sarcoma
Committee protocols during the last 20 years, in order to obtain
information to establish a more adequate diagnostic and therapeu-
tic approach. Procedures. Data were derived from the AIEOP STSC
database and reviewed for the purpose of this study. Results. From
1988 to 2008, among 189 patients with metastatic RMS, we identi-
fied 7 (3.7%) patients with RMS with breast involvement at diagnosis.
All patients were females, aged 13–17 years with alveolar histology
and multiple metastasis sites (2–5). The primary tumor was located
in the extremities in 3/7 patients. In spite of intensive treatment no
patient survived. The cause of treatment failure was distant relapse
in six patients, including two on the mammary region. Treatment
data analysis revealed that local measures to control breast lesions
were used in only two patients. Conclusions. Our data suggest that
investigations of the mammary region should be part of the usual
diagnostic workup in adolescent girls with alveolar RMS, especially
if the primary tumor arises in the extremities. New and more effec-
tive strategies are needed to improve the outcome of these patients
including aggressive local measures to control breast disease. Pediatr
Blood Cancer. 2010;55:1306–1309.
© 2010 Wiley-Liss, Inc.
breast metastasis; childhood solid tumors; outcome; rhabdomyosarcoma; treatment
Primary breast tumors are extremely rare in pediatric age. There
are a number of malignancies that may give rise to metastasis in the
breast, however. Hematological neoplasms, such as lymphoma and
leukemia, and soft tissue sarcoma, especially rhabdomyosarcoma
(RMS), are the most common extra-mammary tumors involving the
RMS is a high-grade malignant skeletal muscle tumor that rep-
resents approximately 4% of malignancies in children. Distant
metastases are discovered at diagnosis in approximately 20% of
children, more frequently in lungs, bone marrow, bones, and distant
lymph nodes. Breast location of RMS is uncommon and has been
reported in up to 6% of patients with metastasis [1,4–6].
Because they are very unusual, breast lesions from RMS may
be difficult to diagnose and treatment is not well established, espe-
cially in terms of local measures. To add further information on this
condition, we report on a series of seven patients with RMS breast
the protocols of the Soft Tissue Sarcoma Committee (STSC), affil-
iated with the Associazione Italiana di Ematologia ed Oncologia
PATIENTS AND METHODS
From January 1988 to December 2008, 189 patients with
metastatic RMS were registered in three consecutive protocols,
MMT4, RMS4.99, and EpSSG RMS2005. Histology was prospec-
tively reviewed by the STSC Pathology Panel and 107 tumors were
sub-classified as alveolar. Clinical and treatment details of patients
with breast metastasis were reviewed for this study. Informed
consent according to institutional guidelines was obtained for all
At diagnosis the primary tumor was imaged by computed
tigations at diagnosis included chest and abdomen CT, radionuclide
bone scan, bone marrow smears and biopsies, and CSF cytology for
parameningeal RMS. No specific recommendations were given to
investigate breasts for tumor involvement.
ing of a 3 or 4 cycles of the CEVAIE regimen, that is, carboplatin,
treatment and subsequent high-dose chemotherapy with stem cell
rescue . One hundred nine children were enrolled from 1996 to
the CEVAIE or IVADo (IVA plus doxorubicin) regimens followed
with vincristine, actinomycin-D, and cyclophosphamide . Nine-
1Pediatric Hematology and Oncology Unit, “G. Di Cristina” Chil-
dren’s Hospital, Palermo, Italy;2Department of Pediatric Hematology
and Oncology, University of Padua, Padua, Italy;3Pediatric Oncol-
ogy Unit, National Institute of Cancer, Milan, Milan, Italy;4Unit of
Pediatric Hematology and Oncology, G. Gaslini Institute, Genoa, Italy;
5Department of Pediatric Hematology and Oncology, University of
Cagliari, Cagliari, Italy;6Pediatric Hematology and Oncology Unit,
7Department of Pediatric Hematology and Oncology, University of
Catania, Catania, Italy;8Pediatric Surgery, Department of Pediatrics,
University of Padua, Padua, Italy
Grant sponsor: “A.S.L.T.I.-Liberi di crescere” Onlus.
Conflict of interest: Nothing to report.
*Correspondence to: Paolo D’Angelo, Unit` a Operativa di Oncoema-
tologia Pediatrica, Ospedale dei Bambini “G. Di Cristina”, A.R.N.A.S.,
Via Benedettini n. 1, 90134 Palermo, Italy.
Received 27 April 2010; Accepted 3 June 2010
© 2010 Wiley-Liss, Inc.
Published online 20 August 2010 in Wiley Online Library
Breast Metastases in RMS1307
TABLE I. Characteristics of the Seven Patients With Breast Metastases at Diagnosis
Time from initial
symptoms to Dx
Site of primary
tumorPtHistology Sites of metastasesClinical characteristics of breast metastases
1 133 monthsAlveolar Right legBone, LN, BM, breast
Bone, LN, BM, left hand,
Bone, LN, breast bilateral
Multiple bilateral nodules (the largest
Single 2 cm nodule in the right breast2 13.72 months Alveolar Retroperitoneal
3 16.910 months AlveolarVaginaMultiple bilateral nodules (the largest
10cm×8cm, on the right breast)
Some nodules in the right breast
Multiple bilateral nodules (the largest
1.5cm in diameter in the right breast)
Multiple bilateral nodules
Two nodules on the left breast (the largest
1.5cm in diameter)
BM, LN, right breast
Bone, BM, breast bilateral
BM, LN, breast bilateral
LN, left breast
Pt, patient; yrs, years; Dx, diagnosis; LN, lymph nodes; BM, bone marrow.
2005 protocol and received four courses of IVADo regimen, fol-
lowed by local treatment, 5 IVA courses and a maintenance phase
with vinorelbine and low-dose cyclophosphamide .
A formal assessment of the response to chemotherapy of the pri-
mary tumor and all metastasis sites had to be done after the initial 3
cycles of chemotherapy in all protocols. Standard response criteria
ease; partial response (PR)=a reduction in tumor size of more than
50% of the sum of the products of the two maximum perpendic-
ular diameters of each measurable lesion; heterogeneous response
(HR)=a PR at one or more, but not all sites, with no progressive
disease; objective response (OR)=a reduction of less than 50%,
but more than 25%, in the sum of the products of the two maximum
perpendicular diameters of each measurable lesion. Stable disease
or a less than 25% reduction in the size of lesions was recorded as
no response (NR). An increase in tumor size or the detection of new
lesions was defined as progressive disease (PD). Response had to
persist for at least 4 weeks after the assessment.
Seven of 189 consecutive patients with metastatic RMS had
evidence of secondary breast involvement at diagnosis, with an
incidence of 3.7%. Patients and tumor characteristics are shown in
The patients were all females, aged 13–16.9 years (median 14
years). The histological subtype was alveolar in all cases and six
of them, in which molecular analysis was ruled out (pts 2–7), had
cation. The primary tumor was located in the extremities in 3 cases
(hand: 2 and leg: 1); other sites were represented by retroperitoneal
region, vagina, left breast; the site of the primary remained unde-
fined in one girl. All patients presented multiple sites of metastasis
with regional or distant lymph nodes involved in 6 children, bone
marrow in 5, and bone in 4 patients. Concerning breast metastasis
6 patients presented multiple lesions and four of them had evidence
of bilateral involvement. Lesions were large (>5cm) in 2 cases
(Table I). Before starting chemotherapy three girls (pts 3, 4 and 5)
underwent breast mass biopsy, while fine needle aspirate and sub-
sequent cytological examination, confirming infiltration by RMS,
was performed in patient 6.
In two cases, the diagnosis of malignancy was seriously delayed
(cases 3 and 7), 10 and 12 months, respectively. In the first case,
the girl did not reveal the vaginal lesion to the physicians, who
focused their attention on the large bilateral mammary nodules. In
the second case, the primary tumor located in the hand was initially
considered a hematoma and the breast nodules, that subsequently
appeared, were considered as fibro-adenomas.
The CEVAIE and the IVADo regimens were administered to
2 and 5 patients, respectively. After initial chemotherapy CR was
evident in 3 and PR in 4 girls. High-dose chemotherapy (HD-CT)
was administered to four patients. One additional patient received
Considering local treatment, six patients received radiotherapy
ment on the breasts was inhomogeneous and was adopted mainly
in cases of evidence of residual tumor after initial chemotherapy:
3 girls were irradiated, 2 underwent surgery, while 3 in CR did not
receive any kind of local treatment. In one case evidence of tumor
progression in the breast after initial chemotherapy precluded the
implementation of local measures.
Surgery consisted of bilateral nodules resection in one case
and was considered complete, while a more conservative approach
Overall, 4 patients showed tumor relapse or progression during
treatment failure occurred in the breast (Table II). All patients died
of disease with a median survival time of 20 months (range 15–48),
showing an extremely poor prognosis in spite of treatment.
RMS more commonly affects the head and neck region, the gen-
itourinary tract and the extremities. The most common metastatic
sites are bone, bone marrow, lung and lymph nodes. In some cases,
In a series of 1,399 females registered from 1972 to 1992, in the
cases of primary breast RMS and seven more cases with breast
metastases at diagnosis.
Pediatr Blood Cancer DOI 10.1002/pbc
1308 D’Angelo et al.
TABLE II. Systemic Treatment and Outcome of the Patients With Breast Metastases at Diagnosis
CT regimen (response)
Local treatment of the PT
Local treatment of breast metastases
Event (phase of treatment)
CEVAIE (CR), HD-CT (CR) No surgery EBRT (40Gy)
Relapse on both breasts and lymph nodes (off
DOD at 40 months
PD on the right breast (during therapy)
DOD at 17 months
IVADo (PR), HD-CT (CR)
Surgery and EBRT (44Gy)
Surgery (complete resection of the
residual lesion in right breast) and
EBRT (40Gy on the left breast)
Relapse on the primary tumor site (off therapy)
DOD at 48 months
No surgery EBRT (48Gy)
Multifocal relapse on primary tumor site,
axillary LN and BM (during therapy)
DOD at 15 months
IVADo (PR), HD-CT (CR)
No surgery EBRT (44Gy)
Multiple bone relapse in the pelvis and spine
DOD at 48 months
RMS 2005 IVADo (CR)
EBRT on both breasts (50.4Gy)
Relapse on the lumbar tract of the spine (during
DOD at 16 months
RMS 2005 IVADo (PR)
Surgery and EBRT (50.4Gy) Surgery (quadrantectomy with
infiltrated margins), EBRT
Relapse in the proximity of the primary tumor
site (during therapy)
DOD at 20 months
of disease; LN, lymph nodes; BM, bone marrow.
of 6.4%. The lower incidence in our study (3.7%) is explained by
the fact that we have considered only patients with breast involve-
ment at diagnosis, while Howarth et al.  included also cases that
developed breast metastases during the whole history of the tumor.
The patients we report share common characteristics: all were
adolescent girls with an alveolar RMS. If we considered only the
group of older females with alveolar histology, the incidence of
breast metastasis at diagnosis would increase to 13.7% (7/51 aged
>13 years). These findings are in agreement with the literature as
the same age range we described and with a striking predominance
of alveolar histology [12–26].
The gender and age range support the hypothesis that the phys-
iologic state of the breast might be a determining factor in the
development of breast metastases . Howarth et al. suggested that
the increased vascularity of the breast, due to the pubertal develop-
ment phase, typical of the adolescent age, is responsible for the
increased risk of hematogenous metastases in this specific site.
The predominance of alveolar histology may be explained by its
propensity to develop metastatic lesions and higher frequency in
adolescence, but may also represent a distinctive pattern of dissem-
Another characteristic of this series seems to be the location
of the primary tumor in the extremities, as in three of our female
patients. This association was more evident in the report from
Howarth et al., in which all seven patients had the primary tumor
located in the extremities. Similar to the IRS study, the site of pri-
mary RMS was confined to the extremities in 8 of 19 cases with
breast metastases, at diagnosis or at first relapse.
up for patients with RMS, this information is important to include
a specific recommendation for adolescent females in clinical pro-
tocols. Mammography has rarely been found helpful because of
the poor image quality due to the dense fibroglandular structure of
breasts in young girls; so ultrasound should be preferred to search
for breast lesions and evaluate if further investigation such as MRI
are needed . Unfortunately, the breast was not an isolated site
of metastasis in our experience, as patients presented two or more
organs involved in disease dissemination. This may be related to a
delay in diagnosis, as shown in a couple of our cases, but also to an
intrinsic tumor aggressiveness.
Few details on treatment can be extrapolated from the previous
published series but the reported outcome was uniformly dismal.
tion of primary tumor in an unfavorable site, defined as extremity
presence of bone or bone marrow involvement, have been associ-
present in our patients. In addition they showed the more aggressive
The implementation of local treatment of metastasis lesions was
difficult in our patients because multiple organs were involved. Six
patients presented a distant relapse, including 2 on the breast, and
this leads us to suppose that more aggressive treatment of breast
lesions may be considered in the attempt to improve prognosis.
Therapy of breast metastasis of RMS may be challenging, however,
because it is not known if the criteria commonly used for breast
Pediatr Blood Cancer DOI 10.1002/pbc
Breast Metastases in RMS 1309 Download full-text
tumors in adults may be adopted. In particular it is not known if
surgery can be conservative and there is concern to irradiate the
mammary region in young women because of the risk of a sec-
ond cancer and deformity. These difficulties are reflected in our
surgery plus external beam radiotherapy in one case and radiother-
In conclusion, although breast metastases in RMS patients are a
rare event our study contributes to the identification of a subgroup
of patients at higher risk. An accurate, clinical and radiographic or
tology especially if the primary tumor arises in the extremities. Due
to their small number, PET scan or breast MRI should be encour-
of aggressive chemotherapy, confirms the need to explore different
treatment strategies in these patients. In the meantime more aggres-
sive local modalities of surgical treatment and/or radiotherapy of
the breast lesions should be recommended.
The authors thank Mrs. Angela Scagnellato for her continuous
support in data processing. This research was supported by a grant
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