Cytologic Diagnosis of Lobular Carcinoma
of the Breast
Experience With 555 Patients in the Rene Huguenin Cancer Center
Emmanuelle Menet, MD
V? eronique Becette, MD
Marianne Briffod, MD
Department of Pathology, Ren? e Huguenin Center,
St. Cloud, France.
BACKGROUND. Fine-needle aspiration generally produces results that are not as
good for lobular carcinoma as the results for ductal carcinoma of the breast. In
this study, the authors evaluated their team’s performance in cytologic diagnosis of
lobular carcinoma over 11 years and analyzed the reasons for diagnostic failure.
METHODS. Cytologic findings were analyzed in 555 consecutive fine-needle cyto-
puncture specimens from women with palpable, invasive lobular carcinoma of
the breast. The authors also examined the influence of the cytologist’s experience,
the clinical tumor size, the histologic subtype, and the histologic grade on diag-
nostic performance. All negative samples were re-examined, along with all sam-
ples that had been obtained during the last year of the study, to refine the
morphologic description of lobular carcinoma.
RESULTS. Malignancy was diagnosed in 68.8% of specimens overall. The indivi-
dual pathologists diagnosed malignancy in from 44.4% to 81.1% of specimens,
depending on their experience. Diagnostic performance was correlated with clini-
cal tumor size, histologic grade, and histologic subtype, and correct diagnoses
were significantly more frequent in pleomorphic subtypes than in ‘‘classic’’ types.
Re-examination of all 32 negative specimens reduced the false-negative rate from
5.8% to 3.8%.
CONCLUSIONS. Despite the pitfalls associated with lobular carcinoma of the breast,
fine-needle cytopuncture remains a useful diagnostic tool before treatment. Fail-
ures can be reduced through experience and by better knowledge of cytologic fea-
tures. Cancer (Cancer Cytopathol) 2008;114:111–7. ? 2008 American Cancer
KEYWORDS: breast, lobular carcinoma, fine-needle aspiration, cytologic diagnosis.
and inexpensive way of diagnosing malignancy in women with
palpable breast tumors. Coupled with physical examination and
imaging, as part of the triple diagnosis, FNA is used by many experi-
enced European and American teams with near-perfect sensitivity.1
However, FNA performs less well on certain types of cancer, includ-
ing lobular carcinoma of the breast.
Invasive lobular carcinoma, after ductal carcinoma, is the most
frequent type of breast cancer and accounts for approximately 5%
to 15% of cases.2Its incidence is increasing, especially because the
recognition of new subtypes that previously were categorized as
ductal carcinomas.3Lobular carcinoma not only has different mor-
phologic characteristics than ductal carcinoma, but it also has a dif-
ferent course, different clinical and radiologic features, and probably
qualifies for specific therapeutic management. FNA fails more fre-
ine-needle aspiration (FNA) is a rapid, safe, minimally invasive,
Address for reprints: Emmanuelle Menet, MD,
Service de Pathologie, Centre Ren? e Huguenin, 35,
rue Dailly, 92210 St. Cloud, France; Fax: (011)
33-1-47 11 15 16; E-mail: firstname.lastname@example.org
Received October 9, 2007; revision received
December 10, 2007; accepted December 19, 2007.
ª2008 American Cancer Society
Published online 25 February 2008 in Wiley InterScience (www.interscience.wiley.com).
quently in lobular carcinoma than in other types of
breast cancer, with failure rates ranging from 4% to
39.5%, depending on the series.4,5This high rate usu-
ally is attributed to inadequate sampling or poor cel-
lularity and to difficulties in interpretation because
of the presence of only mild atypias and more fre-
quent small cells. For the current study, we retro-
cytopunctures of invasive lobular carcinomas that
were sampled at the Rene Huguenin Cancer Center
over an 11-year period to check our team’s perform-
ance in the diagnosis of lobular carcinoma, to iden-
tify correctable sources of failure, and to ensure
cytologic description of these tumors.
of 555 fine-needle
MATERIALS AND METHODS
At Rene Huguenin Cancer Center, from January 1992
to December 2002, 555 patients with palpable, histo-
logically proven, primary, invasive lobular breast car-
cinoma were investigated previously by fine-needle
cytopuncture without aspiration (FNC) for diagnostic
The clinical size of the tumors ranged from
5 mm to 120 mm. According to the Tumor, Lymph
Node, Metastasis (TNM) classification system, this
series included 166 T1 tumors, 258 T2 tumors, 88 T3
tumors, and 43 T4 tumors.
Tissue sections from biopsy or surgical specimens
were stained with hematoxylin-eosin-safran. Lobular
carcinoma was classified based on World Health Orga-
nization criteria as follows: classic, solid, alveolar,
tubulolobular, or pleomorphic. The presence of a duc-
tal component (mixed forms) also was recorded. The
tumors were graded with the Scarff-Bloom-Richardson
(SBR) system, then classified with the modified SBR
account only the 2 nuclear parameters of the SBR, nu-
clear pleomorphism and mitoses, and each is scored
from 1 to 3: Total tumor scores of 2, 3, and 4 indicate
low-grade tumors (MSBR 1), and scores of 5 or 6 indi-
cate high-grade tumors (MSBR 2).
FNC was performed by 8 cytopathologists who
interpreted the slides prepared from their own speci-
mens. Samples were taken with a 23-gauge needle,
without aspiration, at 3 different tumor sites, as
described previously.7Briefly, the needle was inserted
into the lesion, rotated gently, moved back and forth
in different directions, and withdrawn as soon as a
droplet was observed in the hub. The slides were air
dried andstained with
When a concurrent axillary lymph node was palpa-
ble, it was cytopunctured with the same technique.
Since April 1997, at the clinicians’ request and when
The MSBR takes into
possible, part of the sample has been included in a
cytoblock, as described elsewhere for immunohisto-
chemical studies of hormone receptors, Ki67, and
HER2 and, more recently, E-cadherin expression,
when the cytologic aspect was suggestive of lobular
The initial cytologic diagnoses were classified in
5 categories: inadequate, benign, atypical, suspicious
of malignancy, and malignant. To simplify the tables,
we grouped together ‘‘suspicious’’ and ‘‘malignant’’
To identify sources of erroneous interpretation and
inadequate sampling, we examined the influence of
the cytopathologist’s experience, the clinical size of the
tumor, the histologic subtype, and the MSBR grade.
All FNC specimens in the ‘‘benign’’ group were
reviewed subsequently by consensus by 3 of the cy-
topathologists (E.M., V.B., and M.B.). Moreover, all
malignant specimens that were diagnosed in 2002,
which was the last year of the study, were reviewed
to ensure the main cytologic features of lobular car-
cinoma. The SAS statistical package (SAS Institute,
Inc., Cary, NC) was used for statistical analyses.
The cytologic results are summarized in Table 1. In 70
samples (12.6%), the material was considered inade-
quate for cytologic diagnosis. Benignity was diagnosed
in 32 samples (5.8%) and corresponded to false-nega-
tive results. Seventy-one samples (12.8%) were consid-
ered ‘‘atypical’’ either because of poor cellularity or
because atypias were too mild and infrequent to show
malignancy. Malignancy was diagnosed in 382 sam-
ples (68.8%). All samples but 1, which was misdiag-
nosed as lymphoma, were diagnosed as carcinoma. A
diagnosis of lobular carcinoma was suggested in 64 of
these samples (16.7%). Malignancy was suspected in
only 110 of these 382 samples because of only rare
atypia and/or small nuclei.
Regarding the cytologic results in 60 patients
who were recruited in 2002, there were 42 diagnoses
Cytologic Diagnosis of the 555 Lobular Carcinomas
Cytologic diagnosis No. of patientsPercentage
*The value in parentheses indicates the percentage of malignant tumors in which a diagnosis of
lobular carcinoma was suggested.
112 CANCER (CANCER CYTOPATHOLOGY)April 25, 2008 / Volume 114 / Number 2
of malignancy (70%), including 34 diagnoses (56.7%)
that were certain and 8 diagnoses that were ‘‘suspi-
cious.’’ A diagnosis of lobular carcinoma was sug-
gested in 12 of these patients (28.6%). A lobular type
was suggested more frequently in 2002 than in the
remaining group (12 vs 30 patients and 52 vs 288
patients, respectively; P 5.03).
Among the 101 FNC specimens of axillary lymph
nodes, 40 specimens were considered metastatic.
The rate of correct cytologic diagnosis of malignancy
was increased to 69.4% by these findings, indicating
malignancy in 3 specimens in which FNC material
from the breast tumor had been ‘‘insufficient’’ (1
specimen) or only ‘‘atypical’’ (2 specimens). Between
April 1997 and late 2002, 46 cytoblocks that were
prepared from breast tumor FNC specimens and, in
a few instances, from a concurrent metastatic lymph
node were considered satisfactory for immunohisto-
Influence of the Cytopathologist’s Experience
The performance of the 8 cytopathologists with
respect to the diagnosis of malignancy ranged from
44.4% to 81.1%. The most experienced cytopatholo-
gist performed 201 cytopunctures, and the least
experienced performed 10. The most experienced
cytopathologist performed best, as expected.
To avoid a bias linked to the respective percent-
age of small tumors sampled by each cytopatholo-
gist, for each team member, we compared the
percentage of ‘‘inadequate’’ results for T1 tumors
with the percentage of inadequate results for all
tumors. The 2 cytopathologists with the best overall
results had very similar percentages of inadequate
samples for T1 tumors and for all tumors (4% for 1
and 8% in the other), whereas the other team mem-
bers had higher percentages of ‘‘inadequate’’ results
for T1 tumors than for all tumors.
Influence of Clinical Size
The rate of correct diagnosis rose significantly with
the tumor size from 56.6% for T1 tumors to 86% for
T4 tumors (P 5.0002) (Table 2). In contrast, the fre-
quency of ‘‘inadequate’’ results that were correlated
negatively with tumor size fell from 22.3% for T1
tumors, to approximately 9% for T2 and T3 tumors,
and to 2.3% for T4 tumors (P 5.0001). A similar
(P 5.082; nonsignificant).
Influence of the Histologic Subtype
Forty-nine lobular carcinomas were pleomorphic
(Table 2). The proportion of pleomorphic tumors
diagnosed as malignant was 89.8%. Cytopuncture
was significantly more accurate for pleomorphic sub-
type (44 vs 5 tumors) than for other subtypes (338 vs
168 tumors; P 5.00091). In contrast, the lobular type
was suggested less often for these pleomorphic sub-
types than for other subtypes, especially the classic
type (6.8% vs 18%).
The other histologic variants, which were less
numerous in this series, had little influence on the
cytologic results. Ten carcinomas were tubulolobular
(6 malignant, 1 atypical, 1 benign, and 2 inadequate),
4 were solid and/or alveolar (3 malignant and 1
inadequate), and 4 were mixed (both lobular and
ductal: 2 malignant, 1 atypical, and 1 inadequate).
Furthermore, 5 tumors were associated with a ductal
carcinoma in situ component, and all were diag-
nosed as malignant by cytopuncture.
Influence of the Histologic Nuclear Grade (MSBR)
Five hundred forty-nine carcinomas could be graded,
and 6 could not. The MSBR grade was 1 in 493
tumors (89.8%) and 2 in 56 tumors (10.2%).
Comparison of the cytologic diagnoses with the
MSBR histologic grade (Table 2) indicated that cor-
rect cytologic diagnoses were significantly more fre-
quent for high-grade tumors (MSBR 2) than for low-
grade tumors (MSBR 1; (49 of 56 tumors vs 327 of
493 tumors, respectively; P 5.0012). The percentages
of ‘‘inadequate,’’ ‘‘benign,’’ and ‘‘atypical’’ diagnoses
clearly were higher for low-grade tumors (13.4%,
6.5%, and 13.8%, respectively) than for high-grade
tumors (7.1%, 0%, and 5.4%, respectively). Among
Cytologic Diagnosis With Tumor Size, Histologic Subtype,
and Histologic Nuclear Grade
patients InadequateBenign Atypical Malignant*
MSBR indicates the modified Scarff-Bloom-Richardson grading system.
* Values in parentheses indicate the number of malignant tumors for which a diagnosis of lobular
carcinoma was suggested.
Cytologic Diagnosis of Lobular CA/Menet et al. 113
the 49 pleomorphic carcinomas, 32 tumors were
MSBR grade 2 (65.3%), and 17 were MSBR grade 1
Review of False-negative Samples
The percentage of false-negative samples initially
was 5.8% overall and ranged from 0% to 15% (me-
dian, 4.7%), depending on the cytopathologist. A
slide review of the 32 false-negative samples con-
firmed the absence of suspicious or malignant cells
in 21 samples and rectified the diagnosis in 11 sam-
ples. Among these 11 samples, suspicious cells were
observed in 8 samples, 1 sample was considered
‘‘suspicious,’’ and the other 2 samples were reclassi-
fied as ‘‘malignant.’’ The pitfalls noted during this
slide review included poor cellularity, very fragile
samples (often crushed), the presence of only mild
atypia, small nuclei, or intermingling with benign-
Reviewing slides from the 42 malignant samples that
were diagnosed in 2002, we observed that the back-
ground often was thick, eosinophilic, and sometimes
had crushed material interspersed with fatty vacuoles
and small, fibrous stromal fragments (Fig. 1). The
cells were isolated and dispersed or were grouped to-
gether in small and poorly cohesive clusters with
occasional single-cell alignments (Fig. 2). Intracyto-
plasmic vacuoles with a targetoid appearance some-
times compressed and indented the nucleus (Fig. 3).
The shape of the nuclei was rather characteristic,
with irregular angular, triangular, indented, and occa-
sionally budding nuclei (Fig. 4).
In the literature, FNA reportedly diagnoses malig-
nancy correctly in 63% to 94.8% of all breast cancers
(median, 84%), depending on the team.9,10This high
rate is accounted for mainly by ductal carcinoma,
which is the most common type of breast carcinoma,
whereas sensitivity is lower for some other types,
focused on FNA diagnosis of lobular carcinoma.
According to the literature, the cytologic features
of the ‘‘classic’’ form is well defined: It has small,
FIGURE 1. This photomicrograph shows eosinophilic background, small
fibrous fragments, altered material interspersed with fatty vacuoles, few
malignant cells with eccentric nuclei, and intracytoplasmic vacuole with
targetoid appearance (May-Gruenwald-Giemsa [MGG] stain; original magnifi-
FIGURE 2. Single-cell alignment (Indian file) (MGG stain; original magnifi-
FIGURE 3. Intracytoplasmic vacuole with typical targetoid appearance
(MGG stain; original magnification, 340).
114 CANCER (CANCER CYTOPATHOLOGY) April 25, 2008 / Volume 114 / Number 2
monomorphous cells with mild atypia and often has
intracytoplasmic vacuoles with targetoid appearance,
usually isolated or arranged in single-cell files or in
small, loose clusters.11,12The diagnosis of lobular
carcinoma often is hindered by the absence or mar-
ginality of these criteria, especially on poorly abun-
The rate of false cytologic diagnosis of benignity
in lobular carcinoma varies from 1 team to another
between 4% and 32%.4,13–19Our rate of 5.8%, there-
fore, is relatively low. The false-negative results corre-
sponded either to ‘‘true cytologic-negative’’ samples,
which contained only benign epithelial cells because
of possible missampling; or to the presence of be-
nign cells linked to associated fibrocystic change; or
to misinterpretation of tumor cells with rare and
mild atypia. All 32 ‘‘benign’’ samples in our series
were reviewed by 3 members of the team, who con-
firmed only 21 samples, reducing the false-negative
rate from 5.8% to 3.8%. Other research groups also
have reported a reduction in the false-negative rate
after a slide review.17,18
Overall, the percentage of ‘‘inadequate’’ samples
was approximately 12.8% in our series. Other authors
have reported an over-representation of lobular car-
cinoma among ‘‘inadequate’’ samples,
because of poor cellularity and mild cytonuclear
atypia.20,21In our team, the performance in sampling
improved over the years, and the proportion of
‘‘inadequate’’ samples fell to only 11.7% in 2002.
We observed a sensitivity for malignancy of
68.8% overall (382 samples). This rate rose to 69.4%
when concurrent FNC of palpable metastatic axillary
lymph nodes was taken into account. Our results are
similar to those obtained in other series, in which
89%.14,15However, we must point out that we took
into account only palpable tumors that had been
sampled without sonographic guidance, whereas this
is not always mentioned in other series.15,17,18The
proportion of our unequivocally malignant diagnoses
rose to 56.7% in 2002 compared with 48.1% for the
remaining previous years. Similarly, regarding malig-
nant cytologic diagnoses, a diagnosis of lobular type
was suggested more frequently in 2002 (28.6%) than
for the remaining series (15.3%). This improvement
probably can be attributed to the cytopathologists’
The rate of correct diagnosis was influenced by
the cytopathologist’s experience, as expected, and ran-
ged from 44.4% to 81.1%. Lack of experience generally
is reported as an important source of false-negative
results.22–24The importance of the cytopathologist’s
experience was confirmed in our study by the low
and very stable rate of ‘‘inadequate’’ results obtained
by the 2 most experienced team members, whatever
the size of the tumor, whereas their colleagues’ accu-
racy was influenced by tumor size.
depends globally on the clinical size of the tumor.
The rate of ‘‘inadequate’’ results in our series was
22.3% for T1 tumors but only 2.3% for T4 tumors.
These results are consistent with those published
Similar to what was reported by Hwang et al.,4in
most patients who had variants of lobular carcinoma,
we usually obtained sufficient material for an unequi-
vocal diagnosis of carcinoma. Among these different
histologic subtypes of lobular carcinoma, the pleo-
morphic type differs from the classic type. Pleo-
morphic lobular carcinoma
approximately 15 years ago. On the basis of histo-
pathologic criteria, pleomorphic lobular carcinoma is
defined as an invasive carcinoma with the architecture
of invasive lobular carcinoma but with very particular
cytologic characteristics (marked atypia, high mitotic
activity, and high nuclear grade). It is important to
identify this form correctly, because it is more aggres-
sive and carries a worse prognosis than the classic
type.25,26Diagnosis of malignancy is easier in pleo-
morphic lobular carcinoma because of the presence of
more marked atypia and because cellularity generally
is higher in cytopuncture samples, as reflected in our
series by the far lower percentage of ‘‘inadequate’’
results (6.1%) relative to classic forms (13.2%). Other
authors also have reported higher rates of correct diag-
nosis of malignancy with this subtype of lobular carci-
noma.4,11In contrast, it is more difficult to recognize
the lobular type of these tumors, because the cytologic
formalignancyrangedfrom 62% to
FIGURE 4. Indented and budding nuclei in a pleomorphic subtype (MGG
stain; original magnification, 340).
Cytologic Diagnosis of Lobular CA/Menet et al.115
aspect is more suggestive of poorly differentiated duc-
tal carcinoma.11This pitfall emerged clearly in our se-
ries, because a diagnosis of lobular carcinoma was
raised less frequently for the pleomorphic type (6.8%)
than for ‘‘classic’’ forms (18%).
Nearly 90% of the lobular carcinomas in our se-
ries had low nuclear grade, and only 10.2% were
high-grade tumors. Carcinomas with high nuclear
grade corresponded mainly to variants of lobular car-
cinoma and especially to the pleomorphic type4; the
latter represented 57% of high-grade tumors in our
series, and [65% of the pleomorphic lobular carcino-
mas were MSBR grade 2. Furthermore, low-grade
carcinoma appeared to be over-represented among
cytologically ‘‘benign’’ and ‘‘inadequate’’ samples,
both in our series (94% and 100%, respectively) and
in the literature.4
Overall, our results confirm that the cytologic di-
agnosis of malignancy is more difficult in lobular
carcinoma than in ductal carcinoma, even in the
hands of experiencedcytopathologists.
nately, in the case of lobular carcinoma, physical ex-
amination and imaging studies also are less accurate
than for most other carcinomas.19
In addition to diagnosing malignancy, it is im-
portant to attempt to identify the lobular type of
these carcinomas. In our global series, lobular carci-
noma was suggested in 16.7% of ‘‘malignant’’ sam-
ples based solely on the morphologic features.
However, cytologic characteristics are not fully speci-
fic for lobular carcinoma, because they sometimes
are observed (especially small nuclei) in other types
of breast carcinoma, such as ductal carcinoma.27
Thus, some typical features, such as intracytoplasmic
vacuoles with a targetoid appearance, in fact may
correspond histologically to ductal carcinoma (Fig.
5); in our experience, this confusion arises in nearly
20% of samples (data not shown). The lobular type
of breast carcinomas can be identified more accu-
rately by using cytoblocks when the samples are suf-
ficiently cellular, particularly with anti-E-cadherin
immunohistochemistry.8When the tumor cells are
negative for E-cadherin (Fig. 6), then a diagnosis of
lobular carcinoma can be made with confidence.
This not only improves the sensitivity of cytologic di-
agnosis in some patients but also opens the way to
more appropriate patient management. Indeed, lobu-
lar carcinoma differs from ductal carcinoma by its
higher frequency of bilaterality, its clinical course,
and its poor chemosensitivity (especially to neoadju-
vant chemotherapy) and probably requires a different
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FIGURE 5. Intracytoplasmic vacuole with targetoid appearance in a ductal
invasive carcinoma (MGG stain; original magnification, 340).
FIGURE 6. Cytoblock: malignant E-cadherin-negative cells with internal
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