original article
Annals of Oncology 19: 682–687, 2008
doi:10.1093/annonc/mdm546
Published online 28 November 2007
Metastases to the breast: role of fine needle cytology
samples. Our experience with nine cases in 2 years
F. Fulciniti1*, S. Losito1, G. Botti1, D. Di Mattia1, A. La Mura1, C. Pisano2 & S. Pignata2
1
Section of Pathology, Cytopathology Service; 2Department of Gynecological Oncology, National Cancer Institute, Fondazione G. Pascale, Naples, Italy
Received 24 October 2007; revised 26 October 2007; accepted 27 October 2007
original
article
Background: The increased survival due to the introduction of effective antineoplastic regimens has caused
a modification of the natural history of numerous malignancies. Follow-up of neoplastic patients often includes the
evaluation of masses in various body sites by fine needle cytology (FNC) in order to rule out cancer recurrence.
Besides primary neoplasms, the breast can host a number of metastases: these rarely do have a typical presentation,
so FNC is requested for their cytomorphological assessment.
Patients and methods: This report describes nine consecutive cases in which a cytopathological diagnosis of
metastasis to the breast was carried out on FNC samples.
Results: Primary sites were identified on cytomorphological and immunocytochemical bases and were represented
by the ovary (three cases), melanoma (two cases), endocervix (one case), endometrium (one case), lung (one case)
and prostate (one case).
Conclusion: The cytopathological diagnosis of metastatic neoplasms to the breast is not always straightforward,
especially in the absence of a clinical history of cancer. The usage of improved cytopathological criteria combined with
immunocytochemistry may be of great diagnostic help in the identification of breast metastases.
Key words: breast neoplasms, clinical cytology, diagnostic cytopathology of tumors, fine needle cytology,
metastases to the breast
introduction
case reports
Fine needle cytology (FNC) is frequently requested on palpable
breast masses developing in neoplastic patients [1–9]. Breast
involvement by metastatic neoplasms versus primary
malignancies is relatively rare (0.5%–6.6%) [10, 11], but it
could turn out to be higher by the systematic usage of
combined imaging techniques and FNC. While FNC is a fast
diagnostic tool in detecting malignancy, the cytopathological
diagnosis of metastatic neoplasms to the breast is not always
straightforward, mainly due to the paucity of definite
mammographic criteria and to the often confusing clinical–
cytological picture of metastases. Another frequent problem
in the clinical practice is the necessity to exclude synchronous
and metachronous neoplasms involving the breast in the
clinical setting of genetically determined multiple primary
malignancies.
The aim of this paper is three-fold: to describe our findings
in nine cases of metastatic neoplasms to the breast, to analyze
the diagnostic criteria useful for their identification and to
discuss the utility of classical radiological criteria on the final
diagnosis where feasible.
The database of the Cytopathology Laboratory and Service
was searched for all cases in which a cytopathological
diagnosis of metastasis to the breast had been formulated
from January 2005 to July 2007. Nine such cases were
found out of 1140 new diagnoses of primary breast
carcinoma diagnosed by FNC in the same period
(0.78%).
All FNC were carried out on outpatients on palpable
lesions, using a 23-25G needle, without suction. The
obtained material was smeared onto four or more slides
and stained with Diff-Quik (DQ) after air drying or
with Papanicolaou (PAP) after wet fixation in 95% ethanol.
Spare, stained or unstained ethanol-fixed, air-dried smears
or needle washings fixed in Cytolyt and processed as
liquid-based preparations were processed for
immunocytochemistry (ICC) by using an indirect
immunoperoxidase-based kit (LSAB, Dako, Milan, Italy),
commercially available mAbs and polyclonal antibodies
and a semiautomated immunostainer (Dako) (see Table 1
for specifications). As the subjects were outpatients, they
usually carried their imaging studies with them, so the
imaging results were only transcribed by the cytopathologist
taking the fine needle sample and very little documentation
was available for photography.
*Correspondence to: Dr F. Fulciniti, Section of Pathology, Cytopathology Service,
National Cancer Center, Fondazione G. Pascale, Via Mariano Semmola 1, I-80131
Naples, Italy. Tel/Fax: +39-081-5903849; E-mail: [email protected]
ª The Author 2007. Published by Oxford University Press on behalf of the European Society for Medical Oncology.
All rights reserved. For Permissions, please email: [email protected]
original article
Annals of Oncology
Table 1. Clinicopathological data of nine patients with breast metastases
Case Sex Age Site and
no.
diameter
History
Therapy
Latency
Cytological
diagnosis
IIC
Histological
diagnosis
1
F
59
R, UIQ, 1.5 cm
a-1IF
2 years
Metastatic melanoma
(mammary LN)
F
52
R, UOQ and
LOQ, 1.5,
2.5 cm
a-1IF
4 years
HMB45, S-100
IDC (pT2) +
metastatic melanoma
(mammary LN)
3
M
70
R, paraareolar
G2 Prostatic
carcinoma
Antiandrogens
+ RT
3 years
PSA
Metastatic carcinoma
of the prostate
4
F
78
R, UOQ
Stage 3, G2
inflammatory
Endometrial
mastitis
carcinoma
Adjuvant CT,
4 years
Capecitabine
ER, PR, p53
ND
5
F
49
R, UOQ,
L, UIQ
PCT
2 years
6
F
42
CT, RT
2 years
Pigmented
metastatic
melanoma
UOQ: infiltrating
duct carcinoma.
IOQ: amelanotic
metastatic
melanoma
High-grade
metastatic
prostatic
carcinoma
Metastatic
endometrial
carcinoma with
adenosquamous
differentiation
Metastatic serous
carcinoma of
the ovary
Metastatic serous
carcinoma
HMB45
2
Melanoma of
the back Clark’s
stage 3
Melanoma,
scapular
region, Clark’s
stage 3
7
F
53
CT, RT
9 years
8
F
71
CT
2 years
9
F
59
Stage 3 G3
Ovarian serous
carcinoma
R, LIQ
G3 Endocervical
serous
carcinoma
L, LIQ
Stage 3, G3
ovarian serous
carcinoma
R, UOQ,
Stage 3, G3 ovarian
R Ax. LN
serous carcinoma
R, UIQ
No neoplastic
Inflammatory
history
mastitis
hypoplasia
of R lung
Xeloda
Metastatic serous
carcinoma
Metastatic serous
carcinoma
3 months Metastatic lung
adenocarcinoma
CK 7, ER, PR,
ND
Ca 125, WT-1
ER, PR, Her-2
CK 7, Ca 125,
WT-1
Ca 125, ER, PR,
Her-2, WT-1
TTF-1, CEA
G3 endocervical
serous
adenocarcinoma
ND
ND
ND
UIQ, upper inner quadrant; a1-IF, a1-interferon; LN, lymph node; UOQ, upper outer quadrant; IOQ, inner outer quadrant; LOQ, lower outer quadrant;
LIQ, lower inner quadrant; PSA, prostate-specific antigen, CT, chemotherapy, ER, estrogen receptor; PR, progesterone receptor; Ax, axillary; IDC, infiltrating
duct carcinoma; PCT, polychemotherapy; CEA, carcinoembryonic antigen.
cases 1 and 2 : metastatic melanoma
Two females aged 59 and 52 years, respectively, with a previous
history of Clark’s stage 3 melanoma of the back and scapular
region, presented with nodular breast lesions 1.5–2.5 cm in
diameter (Table 1). In case 1, the dense, well-delimited lesion
had been mammographically interpreted as a possible cyst,
while in case 2 two nodules with different mammographic
features had been described: a well-delimited dense lesion in the
lower outer quadrant (LOQ) and a stellate lesion in the upper
outer quadrant (UOQ).
These features corresponded to two different neoplasms in
the same breast: amelanotic metastatic melanoma in the LOQ
and ordinary infiltrating duct carcinoma in the UOQ. Both
lesions were correctly recognized by FNC in this case. In both
cases, the cytological diagnosis of metastatic melanoma was
rather easy and ICC was carried out as an ancillary test with
confirmatory aim (Figure 1A–C). Histopathological
examination disclosed, in both cases, metastases of melanoma
within intramammary lymph nodes. In case 2, a G2 infiltrating
duct carcinoma was also present in the OUQ. Four of 27
Volume 19 | No. 4 | April 2008
axillary lymph nodes contained metastatic deposits of duct
carcinoma.
case 3: prostatic carcinoma
A 70-year-old man with a 3-year history of prostatic carcinoma
presented with a hard periareolar nodule in his right breast.
FNC was carried out and the cytopathological picture showed
a G2 carcinoma with frequent glandular and acinar pattern and
intense cellular necrosis. ICC stain for prostate-specific antigen
(PSA) was positive in the cytoplasm of most of the wellpreserved neoplastic cells (Figure 2A–C). Further computed
tomography and magnetic resonance imaging work-up
demonstrated the presence of widespread abdominal and
mediastinal lymphadenopathy and multiple osteolytic lesions
of the axial skeleton; total serum PSA was 1020 ng/ml. The
patient was lost to follow-up after diagnosis.
case 4: endometrial adenocarcinoma
A 78-year-old lady was sent for FNC of a poorly defined mass
in the UOQ of her right breast associated to skin dimpling,
doi:10.1093/annonc/mdm546 | 683
original article
Annals of Oncology
Figure 1. Fine needle cytology sample, case 2 (Table 1). Amelanotic melanoma: note the dispersed population of (A) epithelioid and (B) fusiform cells
typical of the lesion. (C) Immunocytochemistry (ICC) for HMB45 showing diffuse cytoplasmic positivity of the neoplastic cells. (A) Diff-Quik, medium
power; (B) Papanicolaou, medium power; (C) ICC, high power.
Figure 2. Fine needle cytology sample, case 3: metastatic prostatic carcinoma. (A) A loose group of atypical glandular cells of medium size can be seen in
a necrotic background. (B) The same cells show evidence of cytoplasmic secretion on Papanicolaou (PAP)-stained smear. Notice their prominent nucleoli.
(C) Liquid-based cell preparation from the same case. Immunocytochemistry (ICC) stain for prostate-specific antigen showing diffuse cytoplasmic positivity
of the neoplastic cells. (A) Diff-Quik, medium power; (B) PAP, medium power; (C) ICC, medium power.
cutaneous redness and marked tenderness on palpation. The
lady had a 4-year history of stage 3, G2 endometrial
adenocarcinoma. The cytopathological picture showed
monolayered sheets and branching glandular clusters of small
cylindrical cells in a necrotic background. They had small
nucleolated nuclei and eosinophilic cytoplasm with an overall
‘endometroid’ appearance; focal areas of adenosquamous
differentiation were observed, with larger polygonal cells with
dense cytoplasm. Diagnostic smears were tested for estrogen
receptor (ER) and progesterone receptor (PR) with positive
result for both in >75% of the neoplastic cells and for p53
protein, that was over-expressed (Figure 5A–C). A diagnosis of
metastatic endometrial adenocarcinoma was made. The patient
died shortly after with widespread disease.
cases 5–8: ovarian and endocervical serous
carcinomas
Four females—age range 42–71 (median age 47.5) years—were
sent for cytopathological evaluation of bilateral well-delimited
breast nodules (case 5) or single stellate mammographic
densities (cases 6–9). In case 9, an omolateral axillary
lymphadenopathy was also sampled by FNC.
All patients had a previous history of stage 3 ovarian G2 or
G3 serous carcinoma (cases 5, 7, 8) or stage 3 endocervical G3
serous carcinoma (case 6, Table 1). After surgery the patients
had been treated with polychemotherapy. In cases 6 and 7,
debulking radiotherapy had also been administered to the
pelvis (30–45 Gy).
684 | Fulciniti et al.
The cytopathological picture in these cases showed a medium
cell epithelial malignancy arranged in papillary clusters (Figure
3A–C). The neoplastic cells displayed round nuclei with evident
nucleoli and a moderate quantity of greyish cytoplasm in DQstained smears. In case 5, several well-formed psammomatous
microcalcifications were evident both in the DQ- and in the
PAP-stained smears (Figure 3C). ICC stains demonstrated
cytoplasmic positivity for Ca 125 (Figure 4C) and diffuse
nuclear staining for WT-1.
In case 8, the cytological picture, in both the breast and the
lymph node samples, showed a medium cell epithelial
malignancy organized as single cells, sheets and trabecular or
papillary clusters (Figure 4A–C). The neoplastic cells had
centrally placed, nucleolated round nuclei; the cytoplasms were
moderately developed, well-delimited, greyish in DQ-stained
and transparent to pinkish in PAP-stained smears. ICC stains
were carried out on additional wet-fixed smears: these were
negative for ER and PR and for Her-2. Ca 125 and WT-1 stains
were diffusely positive. A final diagnosis of metastatic G3 serous
carcinoma was reached.
case 9: metastatic lung adenocarcinoma
A 59-year-old lady presented with a history of exacerbating
dyspnea and a poorly delimited mass in the upper inner
quadrant of her right breast, with skin dimpling and reddening.
The lady had received a diagnosis of hypoplasia of the right
lung many years before. At the moment FNC sample was taken,
she had a massive right-sided pleural effusion and was febrile.
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Annals of Oncology
original article
Figure 3. Fine needle cytology sample, case 5, metastatic low-grade serous adenocarcinoma of the ovary. (A) A group of carcinomatous cells of medium
size with distinct papillary organization can be observed. (B) the neoplastic cells show small single nucleoli and whorl-like configuration within papillary
tips. (C) The same papillary fronds are often centered by orangiophilic psammoma bodies. (A) Diff-Quik, low power; (B) Papanicolaou (PAP), medium
power; (C) PAP, medium power.
Figure 4. Fine needle cytology sample, case 8, metastatic G3 serous adenocarcinoma of the ovary. (A) Some loose papillary fronds of carcinomatous cells
with distinct nuclear atypias can be seen. (B) The papillary organization of the cellular cluster is somewhat enhanced by the immunocytochemical staining
for CK 7. (C) Immunocytochemistry (ICC) stain for Ca 125 displaying diffuse cytoplasmic positivity of the neoplastic cells. (A) Diff-Quik, medium power;
(B) ICC, low power; (C) ICC, medium power.
Figure 5. Fine needle cytology sample, case 4, metastatic endometrial adenocarcinoma. (A) A cohesive group of carcinomatous cells showing distinct
glandular arrangement with peripheral nuclear palisading. (B) The glandular aggregates suggest an ‘endometrioid’ appearance on Papanicolaou (PAP)stained material. (C) Some cohesive groups of malignant cells show ‘squamoid’ differentiation. (A) Diff-Quik, low power; (B) PAP, low power; (C) PAP, low
power.
The cytopathological picture on the obtained sample showed a G2
papillary adenocarcinoma with numerous reactive osteoclast-like
giant cells (Figure 6A–C). While immunocytochemical staining
for ER and PR were negative, TTF-1 staining showed diffuse
nuclear reactivity in the malignant cells (Figure 6B). A
cytopathological diagnosis of metastatic adenocarcinoma of
lung origin rich in osteoclast-like reactive giant cells was made,
that was confirmed radiologically after pleural drainage.
discussion
Despite the rarity of metastases to the breast, small or more
extensive reports dealing with their cytopathological
Volume 19 | No. 4 | April 2008
presentation have been published by most institutions in which
FNC is routinely adopted as a diagnostic technique [1–9].
Melanomas, lung carcinoma and ovarian carcinoma, together
with hematolymphoid malignancies, rank among the
commonest primary sites, as also reflected in this relatively
small series [10, 11].
In the diagnosis of metastases to the breast, the most
meaningful factors are represented by the clinical history, the
cytopathological picture and the immunocytochemical profile
of the neoplasm. As also in our cases, in fact, the radiological
presentation of metastases may be misleading. In our series,
a previous history of a malignant neoplasm was always present
and this information had an enormous impact on the
doi:10.1093/annonc/mdm546 | 685
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Annals of Oncology
Figure 6. Fine needle cytology sample, case 9, metastatic peripheral lung adenocarcinoma. (A) A group of medium-sized carcinomatous cells showing
complex papillary arrangement can be observed in a clean background. (B) TTF-1 immunocytochemistry (ICC) stain showing distinct nuclear positivity in
all the malignant cells. (C) Carcinoembryonic antigen ICC showing distinct cytoplasmic and membrane positivity in the carcinomatous cells. (A) Diff-Quik,
low power; (B) ICC, low power; (C) ICC, medium power.
formulation of a correct diagnosis. Nevertheless, some
cytopathological differential diagnostic problems in this setting
exist. For instance, a classic issue is the differential diagnosis
between primary breast carcinoma, especially dissociated, highgrade ductal or apocrine type and amelanotic epithelioid
melanoma [1, 3, 6, 8, 9]. Two points may be worthwhile
signaling: the possible help in a correct diagnosis given by the
radiological presentation of a well-delimited opaque nodular
mass in metastatic melanoma (in our cases, this corresponded
to two metastatic intramammary lymph nodes) and, on the
contrary, the negative contribution of keratin immunostaining,
if this is not used in conjunction with other melanoma markers
in a given situation since, as it is known, some cases of
epithelioid melanoma may express cytokeratin intermediate
filaments [5, 12, 13]. The issue may be further complicated by
the association of metastatic melanoma and breast carcinoma,
as in case 2 of our series (Table 1). This association has also
been described in the literature [14].
The next numerous group of metastases were represented by
ovarian (and endocervical) serous papillary carcinomas. With
this respect, among the useful diagnostic criteria, were the
presence of psammoma bodies and the papillary architecture of
the cell clusters. The immunocytochemical stains for Ca 125
and WT-1 had a 100% efficiency in this group of tumors.
Metastatic papillary carcinomas should be cytologically
distinguished by primary papillary and micropapillary
carcinomas of the breast. The latter represents a complex group
of lesions for cytopathologists that has been well addressed to in
the literature [15]: we would only like to underline the fact that
psammoma bodies in combination with papillary epithelial cell
groups have been found also in primary mucinous breast
carcinomas [16, 17] and stress the usefulness of AE1–AE3 or
MUC 1 immunocytochemical stain to detect the so-called
‘inside out’ pattern of cytoplasmic positivity in micropapillary
carcinomas [18, 19].
Prostate carcinoma is one of the commonest metastases to
the breast in males and its diagnosis might be difficult if one
ignores the clinical history or if the metastasis is precessive with
repect to the primary tumor [2]. PSA ICC was of great help in
our case, due to the intense cellular necrosis, partly obscuring
the cytological presentation.
With regard to the clinical presentation, we were struck by
the ‘inflammatory mastitis’ presentation of metastatic
686 | Fulciniti et al.
adenocarcinoma of, respectively, endometrial and lung origin.
Similar clinical pictures have been already recorded in the
cytological [20] and radiological literature [21] and are
pathologically explicable with tumor spreading into superficial
dermal lymphatic vessels.
Our findings further confirm the relative rarity of metastatic
involvement of the breast also in an outpatient setting and
underline the primary role of cytomorphological and
immunocytochemical work-up in the diagnostic assessment of
secondaries to the breast.
funding
This paper was made possible by a generous donation by the
Lega Italiana per la Lotta ai Tumori, Sezione di Napoli.
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