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CANCER
33
CYTOPATHOLOGY
Cytologic Features of Proliferative Breast Disease
A Study Designed to Minimize Sampling Error
Andra R. Frost, M.D.1
Sana O. Tabbara, M.D.2
Linda A. Poprocky, C.T.2
Heidi Weiss, Ph.D.1
Mary K. Sidawy, M.D.2
1
University of Alabama at Birmingham, Birmingham, Alabama.
2
The George Washington University, Washington,
DC.
BACKGROUND. Assessment of cytologic features that allow accurate classification of
proliferative breast disease has been hampered by sampling errors when fineneedle aspirations have been compared with their corresponding histologic sections.
METHODS. To allow for optimal cytohistologic correlation, 2 smears (1 hematoxylin
and eosin–stained and 1 Diff-Quik-stained) were prepared from each of 98 breast
biopsies without mass lesions and compared with the corresponding histologic
sections of the scraped area. Each smear was reviewed in a blinded fashion and
assessed for cellularity, background elements, cytoarchitectural features of cell
groups, and nuclear features by 2 reviewers. Smears were then classified as nonproliferative breast disease (NPBD), proliferative breast disease without atypia
(PBD) or with atypia (PBDA), or DCIS, based on review of the corresponding
histologic sections.
RESULTS. When comparing NPBD/PBD (n ⫽ 86) with PBDA/DCIS (n ⫽ 12), smears
from PBDA/DCIS were significantly (by the Fisher exact test or Wilcoxon rank sum
P values with adjustment for multiple comparisons) more likely to be cellular;
contain single cells and necrosis; exhibit nuclear overlap and cytoplasmic vacuoles;
have large nuclei, macronucleoli, pleomorphism, clumped chromatin, and hyperchromasia; and were less likely to have complex cell groups, monolayers, swirling,
cohesion, and myoepithelial cells in epithelial sheets and the smear background.
When NPBD (n ⫽ 53) and PBD (n ⫽ 33) were similarly compared, smears from PBD
were more likely to exhibit larger and more complex cell groups, but they were
otherwise similar to smears from NPBD.
CONCLUSIONS. There are many cytologic features that will allow a distinction of
NPBD/PBD from PBDA/DCIS, but relatively few that can aid in separating NPBD
from PBD. Cancer (Cancer Cytopathol) 2000;90:33– 40.
© 2000 American Cancer Society.
KEYWORDS: cytology, breast, nonproliferative breast disease, proliferative breast
disease, ductal carcinoma in situ.
Abstract presented in part at the 87th Annual
Meeting of the United States and Canadian Academy of Pathology, Boston, Massachusetts, March
1998.
Address for reprints: Andra R. Frost, M.D., Department of Pathology, University of Alabama at Birmingham, 619 South 19th Street, KB 506 Birmingham, Alabama 35233.
Received April 19, 1999; revision received July 28,
1999; accepted August 6, 1999.
© 2000 American Cancer Society
F
ine-needle aspiration (FNA) of the breast has proven to be a
reliable method of identifying breast carcinomas prior to therapy,
and the diagnostic cytologic features of breast carcinoma are well
established.1– 4 It is also recognized that the cytologic features of
invasive and in situ carcinomas, especially high grade intraductal
carcinomas, are often similar and cannot be reliably distinguished by
FNA.3,5 In the cytologic assessment of proliferative breast disease,
most authors claim good success in distinguishing benign from malignant intraductal proliferations, with most identifying more than
90% of aspirates of ductal carcinoma in situ (DCIS) as either atypical,
probable carcinoma or carcinoma.6 –9 However, a definitive cytologic
34
CANCER (CANCER CYTOPATHOLOGY) February 25, 2000 / Volume 90 / Number 1
diagnosis of carcinoma may be difficult in some cases
of DCIS, particularly low grade DCIS.
Cytologic criteria for identifying and classifying benign proliferative breast lesions, including ductal hyperplasia with and without atypia, and for distinguishing
proliferative from nonproliferative breast lesions in FNA,
have been proposed.7,8,10 –12 Some authors have also
proposed a combination of cytologic and architectural
features of epithelial cell groups.8,10,11,13 Masood et al.7
advocated a scoring system based on the evaluation of
individual cytologic features to classify nonproliferative
breast disease (NPBD), proliferative breast disease without atypia (PBD), proliferative breast disease with atypia
(PBDA), and DCIS. Most authors have reported some
degree of success in identifying and correctly classifying
proliferative breast lesions, but acknowledge that a significant cytologic overlap exists in the continuum of
proliferative lesions.
Underscoring the diagnostic difficulty created by
this degree of cytologic overlap, a recent assessment of
the applicability of the published criteria for identifying nonproliferative and proliferative breast lesions
reported poor diagnostic accuracy and reproducibility
when six cytopathologists with expertise in breast cytopathology were asked to distinguish NPBD, PBD,
PBDA, and DCIS.14 In an attempt to identify cytologic
features that can reliably distinguish PBD from NPBD,
an evaluation of 12 cytologic features in 51 benign
breast aspirates indicated that only the frequency of a
swirling pattern of epithelial cells was significantly
different in PBD and NPBD.15
The development and assessment of cytologic criteria for classifying proliferative breast disease has
been complicated by the heterogeneity of morphologic changes within a given lesion and the lack of
exact histologic correlation related to sampling. This
problem is difficult to overcome completely even
when strict standards of sampling are applied. Sampling errors due to the small size of a proliferative
lesion, or due to the fact that benign PBD may be
present in the midst of nonproliferative fibrocystic
change or carcinoma in situ, may have hindered attempts to identify criteria that reliably distinguish proliferative from nonproliferative breast lesions. In an
effort to overcome the problem of sampling, we have
assessed the cytologic features of proliferative and
nonproliferative breast lesions in cytologic smears
prepared from scraping surgically excised breast tissue.
MATERIALS AND METHODS
Specimen Collection
Ninety-eight excisional breast biopsy specimens without macroscopic mass lesions were included. During
intraoperative consultation, one alcohol-fixed, H &
E–stained and one air-dried, Diff-Quik–stained direct
smear were prepared by scraping a portion of the
specimen consisting macroscopically of fibrous breast
parenchyma. The hematoxylin and eosin (H & E) stain
was chosen because this is the stain routinely used at
the George Washington University Hospital for intraoperative evaluation of alcohol-fixed smears. Although
the Papanicolaou stain is more commonly used in
cytology laboratories for alcohol-fixed specimens,
some laboratories chose to use the H & E stain for FNA
specimens. Both stains allow good evaluation of nuclear detail in alcohol-fixed smears. The area scraped
was separated and placed in a designated cassette.
Subsequently, an H & E–stained histologic section was
prepared from the scraped area, providing optimal
cytohistologic correlation.
Slide Review
The air-dried smear, alcohol-fixed smear, and histologic section for each case were coded, separated from
each other, and reviewed in a masked fashion. Each
slide was reviewed by two cytopathologists (A.R.F.,
S.O.T., or M.K.S.). The smears were assessed and
graded for the following features:
Cellularity was scored as 1 for low cellularity (⬍10
epithelial groups/slide), 2 for moderate cellularity
(10 –30 epithelial groups/slide), and 3 for high cellularity (⬎30 epithelial groups/slide).
A dual population of epithelial cells, apocrine and
nonapocrine, was evaluated as present or absent.
Elements in the smear background, including a
cystic or proteinaceous background, naked bipolar
nuclei (myoepithelial cells), and necrosis, were evaluated as present or absent.
The size of the epithelial groups was graded as 1 if
predominantly small (less than half of a 10⫻ field or
less than approximately 3000 cells), 2 if a nearly equal
mixture of small and large (more than half of a 10⫻
field or more than approximately 3000 cells), and 3 if
predominantly large. The 10⫻ objective used in this
assessment had an ocular field number of FN 20.
The number of single epithelial cells were graded
as 1 if they constituted less than 20%, 2 if they constituted 20 –70%, and 3 if they constituted more than 70%
of epithelial cells. The degree of cohesion of the epithelial cell groups was graded as 1 if loose, 2 if a
mixture of tight and loose groups was present, and 3 if
tight.
The presence or absence of myoepithelial cells
within the epithelial groups was assessed as present or
absent. Myoepithelial cells were recognized as having
spindled to ovoid nuclei that were smaller and darker
that the epithelial cell nuclei.
Cytology of Proliferative Breast Lesions/Frost et al.
Various architectural features of the cell groups
were evaluated. The overall degree of complexity of
the cellular arrangement in the groups was assessed
and scored as 1 if composed of simple sheets with little
folding or branching; 2 if the most complex sheets
exhibited a mild to moderate degree of folding,
branching, lumen formation, or three-dimensionality;
and 3 if the most complex sheets exhibited a marked
degree of folding, branching, lumen formation, or
three-dimensionality. Specific architectural patterns
(i.e., monolayers, cell swirling/streaming, papillae,
slitlike lumens, and cribriform sheets) were assessed
as absent or present. The degree of overlap of nuclei
was scored as 1 for no overlap, and 2 for mild, 3 for
moderate, and 4 for marked overlap.
The nuclear size was graded as 1 if approximately
2 times or less than the greatest dimension of an RBC,
2 if 3– 4 times the greatest dimension of an RBC, and 3
if 5 times or more than the greatest dimension of an
RBC. Nuclear pleomorphism was graded as 1 if the
nuclei were round or oval and uniform in size and 2
for mild, 3 for moderate, and 4 for marked pleomorphism. Nucleoli were graded as 1 if absent, 2 if micronucleoli were present, and 3 if macronucleoli (nucleolus one-fourth of nuclear greatest dimension or
more) were present. The degrees of chromatin clumping and hyperchromasia were assessed only on alcohol-fixed smears and graded as 1 if absent, and 2 if
mild or moderate, and 3 if marked in degree.
Cytoplasmic vacuolization was assessed as
present or absent.
A diagnosis of unsatisfactory, NPBD, PBD, PBDA,
or carcinoma was also made for each slide by the
reviewer, using criteria published in the literature.7,8,10
No equivocal diagnoses (e.g., PBDA vs. carcinoma)
were allowed.
Histologic sections were also reviewed by two pathologists (A.R.F. and M.K.S.) and classified as NPBD,
PBD (i.e., moderate and florid ductal hyperplasia),
PBDA (atypical ductal hyperplasia), and DCIS, using
criteria presented by Page et al.16,17 DCIS was classified as high, intermediate, or low grade using the
criteria presented by Silverstein et al.18 No cases of
invasive carcinoma or lobular neoplasia were included.
Data Analysis
Direct smears and histologic sections were unmasked
and smear diagnoses were compared with the histologic diagnoses. Based on the histologic diagnoses, the
direct smears were then classified as NPBD, PBD, or
PBDA/DCIS, and cytologic features were compared
among these three groups. Because two different reviewers evaluated each direct smear and the review-
35
ers’ assessments were not always concordant, numeric scores were averaged and a feature was
considered to be present even if identified by only one
reviewer. The proportions of cases exhibiting a cytologic feature were compared among diagnostic groups
using the Fisher exact test. Features measured on an
ordinal scale were compared between diagnostic
groups using the Wilcoxon rank sum test. A significance level of P ⱕ 0.05 was required. Analysis was
done separately for air-dried and alcohol-fixed
smears. Because multiple cytologic features were being compared, the sequential rejective bonferroni procedure19 was compared with the Fisher exact test or
Wilcoxon rank sum P values in order to control for the
experimentwise error rate. Because multiple testing of
the different cytologic features results in inflated Type
I error rates, this procedure allows the use of more
conservative P values before declaring significant differences. The result of a Wilcoxon rank sum or Fisher
exact test is significant only if it is less than the sequential bonferroni P value.
RESULTS
Based on the histologic review, the study included
smears from 53 NPBD, 33 PBD, 1 PBDA, and 11 DCIS.
Of the 11 DCIS, 3 were high grade, 6 were intermediate
grade, and 2 were low grade.
Diagnostic Accuracy
The reviewers’ cytologic diagnoses (on air-dried and
alcohol-fixed smears) agreed with the corresponding
histologic diagnosis of NPBD in 58%, PBD in 47%, and
DCIS or PBDA in 82% of the cases. Only low and
intermediate grade DCIS were misclassified cytologically.
Comparison of Cytologic Features
When individual cytologic features of benign breast
disease (NPBD and PBD) were compared with those of
atypical or malignant breast disease (PBDA and DCIS),
there were many features that differed significantly in
degree or frequency on air-dried or alcohol-fixed
smears using the Fisher exact test or the Wilcoxon
rank sum test (Tables 1 and 2). These features included the presence of myoepithelial cells in epithelial
groups, background myoepithelial cells, cell cohesion,
monolayers and cell swirling/streaming in epithelial
groups, micronucleoli, and a greater degree of architectural complexity of cell groups in the NPBD/PBD
group. The PBDA/DCIS group demonstrated greater
cellularity, nuclear overlap, pleomorphism, chromatin
clumping, hyperchromasia, and necrosis; a greater
number of single cells, macronucleoli, and cytoplasmic vacuoles; and a larger nuclear size. However, a few
36
CANCER (CANCER CYTOPATHOLOGY) February 25, 2000 / Volume 90 / Number 1
TABLE 1
Comparison of Cytologic Features in NPBD/PBD and PBDA/DCIS on
Air-Dried Smears
Cytologic feature
Myoepithelial cells in epithelial
groupsa
Background myoepithelial cells
Cellular cohesion
Nuclear size
Nuclear overlap
Nuclear pleomorphism
Single cells
Cell swirling/streaminga
Necrosis
Macronucleoli
Monolayers
Micronucleoli
Complexity of epithelial groups
Cellularity
Cribriform pattern
Papillae
Cytoplasmic vacuoles
Size of epithelial groups
Dual cell population
Slitlike lumenal spaces
Nucleoli absent
NPBD/PBD
% present or
median score
79/84 (94%)
82/86 (95%)
2.5
1.0
2.0
2.0
1.0
61/84 (73%)
3/86 (4%)
10/84 (12%)
44/84 (52%)
68/84 (81%)
1.5
2.0
13/84 (15%)
8/84 (10%)
15/84 (18%)
1.75
27/84 (32%)
18/84 (21%)
8/84 (10%)
PBDA/DCIS
% present or
median score
2/12
3/12
1.0
2.0
3.0
3.25
2.5
2/12
5/12
7/12
1/12
5/12
1.5
2.5
4/12
0/12
3/12
1.75
4/12
2/12
0/12
(17%)
(25%)
(17%)
(42%)
(58%)
(8%)
(42%)
(33%)
(0%)
(25%)
(33%)
(17%)
(0%)
TABLE 2
Comparison of Cytologic Features in NPBD/PBD and PBDA/DCIS on
Alcohol-Fixed Smears
P valueb
c
0.00001
0.00001c
0.0001c
0.0001c
0.0001c
0.0001c
0.0001c
0.00031c
0.00054c
0.00080c
0.0046
0.0068
0.037
0.022
0.216
0.590
0.692
0.777
0.999
0.999
0.999
NPDB: non-proliferative breast disease; PBD: proliferative breast disease without atypia; PBDA: proliferative breast disease with atypia; DCIS: ductal carcinoma in situ.
a
Not statistically significant in alcohol-fixed smears.
b
Based on the Fisher exact test or the Wilcoxon rank sum test.
c
Statistically significant compared with the sequential rejective bonferroni procedure.
of the features were only significant in either air-dried
or alcohol-fixed smears (Tables 1 and 2). These differences remained significant after comparison with the
sequential rejective bonferroni procedure, with the
exception of cellularity, complexity of epithelial cell
groups, and the presence of monolayers and micronucleoli on air-dried smears and the presence of background myoepithelial cells on alcohol-fixed smears
(Tables 1 and 2).
Table 3 presents the comparison of cytologic features between NPBD and PBD using air-dried smears.
Only 2 of the 21 evaluated cytologic features (nuclear
pleomorphism and cell swirling) differed significantly
based on the Fisher exact test or the Wilcoxon rank
sum test. Moreover, none of these features appeared
to be significantly different when assessed with the
more conservative sequential bonferroni procedure.
Using alcohol-fixed smears (Table 4), 5 of the 23 evaluated cytologic features (complexity of epithelial
groups, epithelial group size, the presence of a dual
epithelial cell population, cell swirling, and the presence of slitlike lumens) differed significantly between
Cytologic feature
Macronucleoli
Monolayers
Cellular cohesion
Chromation clumping
Hyperchromasia
Nuclear size
Nuclear overlap
Nuclear pleomorphism
Single cells
Necrosis
Cytoplasmic Vacuolesa
Micronucleoli
Cellularity
Background myoepithelial cells
Myoepithelial cells in epithelial
groups
Dual cell population
Slitlike lumenal spaces
Cribriform pattern
Complexity of epithelial groups
Size of epithelial groups
Papillae
Cell swirling/streaming
Nucleoli absent
NPBD/PBD
% present or
median score
PBDA/DCIS
% present or
median score
P-valueb
1/84 (1%)
58/83 (70%)
3.0
1.0
1.0
1.0
2.0
1.5
1.0
0/84 (0%)
6/83 (7%)
74/83 (89%)
1.5
77/84 (92%)
6/12
1/12
1.5
2.0
2.0
1.75
2.5
3.0
2.25
5/12
6/12
5/12
2.75
7/12
0.00001c
0.00007c
0.0001c
0.0001c
0.0001c
0.0001c
0.0001c
0.0001c
0.0001c
0.0001c
0.00036c
0.0005c
0.0029c
0.0064
78/83 (94%)
29/83 (35%)
16/83 (19%)
1/83 (1%)
1.5
1.5
9/83 (11%)
42/83 (51%)
8/83 (10%)
9/12
7/12
0/12
1/12
1.25
1.5
0/12
5/12
1/12
(50%)
(8%)
(42%)
(50%)
(42%)
(58%)
(75%)
(58%)
(0%)
(8%)
(0%)
(42%)
(8%)
0.061
0.201
0.208
0.238
0.244
0.5739
0.597
0.759
0.999
NPBD: non-proliferative breast disease; PBD: proliferative breast disease without atypia; PBDA: proliferative breast disease with atypia; DCIS: ductal carcinoma in situ.
a
Not statistically significant in air-dried smears.
b
Based on the Fisher exact test or the Wilcoxon rank sum test.
c
Statistically significant compared with the sequential rejective bonferroni procedure.
NPBD and PBD based on the Fisher exact test or the
Wilcoxon rank sum test. However, only complexity
and epithelial group size remained significant after
adjustment for experimentwise error rate.
DISCUSSION
Several reports in the literature document the diagnostic accuracy in identifying DCIS by cytology and
demonstrate great success at recognizing DCIS as carcinoma (invasiveness not specified) with rates approaching 100%.6 –9,11 In contrast, the reported diagnostic accuracy in identifying benign proliferative
breast disease cytologically is more varied. Some authors have reported mediocre success (with overall
cytohistologic correlation in 40 – 64% of cases with
biopsy-proven ductal hyperplasia without atypia),8,10
whereas others have reported somewhat greater success (with 75% and 87% cytohistologic correlation);7,11,15 but the diagnostic accuracy never equals
that for carcinoma. In all reports, the number of cases
Cytology of Proliferative Breast Lesions/Frost et al.
TABLE 3
Comparison of Cytologic Features in NPBD and PBD on Air-Dried
Smears
Cytologic feature
Nuclear pleomorphism
Cell swirling/streaming
Size of epithelial groups
Dual cell population
Cellularity
Background myoepithelial cells
Complexity of epithelial groups
Monolayers
Cytoplasmic vacuoles
Papillae
Necrosis
Myoepithelial cells in epithelial
groups
Nuclear overlap
Single cells
Cellular cohesion
Nucleoli absent
Nuclear size
Macronucleoli
Cribriform pattern
Slitlike lumenal spaces
Micronucleoli
TABLE 4
Comparison of Cytologic Features in NPBD and PBD on AlcoholFixed Smears
NPBD %
present or
median score
PBD %
present or
median score
P valuea
Cytologic feature
1.5
33/52 (63%)
1.5
13/52 (25%)
2.0
52/53 (98%)
1.5
24/52 (46%)
7/52 (14%)
3/52 (6%)
3/53 (6%)
2.0
28/32 (88%)
2.0
14/32 (44%)
2.0
30/33 (91%)
2.0
20/32 (63%)
8/32 (25%)
5/32 (16%)
0/33 (0%)
0.016
0.023
0.054
0.092
0.097
0.155
0.160
0.180
0.242
0.249
0.282
50/52 (96%)
2.0
1.0
2.5
3/52 (6%)
1.0
7/52 (13%)
8/52 (15%)
11/52 (21%)
42/52 (81%)
29/32 (91%)
2.0
1.0
2.5
3/32 (9%)
1.0
3/32 (9%)
5/32 (16%)
7/32 (22%)
26/32 (81%)
0.364
0.414
0.509
0.544
0.670
0.678
0.735
0.999
0.999
0.999
Complexity of epithelial groups
Size of epithelial groups
Dual cell population
Cell swirling/streaming
Slitlike lumenal spaces
Nuclear size
Cellular cohesion
Nuclear pleomorphism
Cellularity
Chromation clumping
Papillae
Nuclear overlap
Hyperchromasia
Single cells
Myoepithelial cells in epithelial
groups
Cytoplasmic vacuoles
Monolayers
Background myoepithelial cells
Cribriform pattern
Necrosis
Nucleoli absent
Micronucleoli
Macronucleoli
NPBD: non-proliferative breast disease; PBD: proliferative breast disease without atypia; PBDA: proliferative breast disease with atypia; DCIS: ductal carcinoma in situ.
a
Based on the Fisher exact test or the Wilcoxon rank sum test.
of PBD has been small, ranging from 9 to 50. Aspirates
of PBD are most frequently misclassified as PBDA or
suspicious for carcinoma but can also be confused
with NPBD.7,8,10,11,15
It is recognized that proliferative breast disease is
a morphologic continuum with overlapping cytologic
and histologic features between lesions within the
continuum. Indeed, significant interobserver variability in the histologic and cytologic classification of proliferative breast disease has been documented. 14,20,21
Such morphologic overlap has hampered our ability to
identify PBD accurately and separate it from NPBD
and PBDA. In a prior evaluation of cytologic features
useful in separating PBD from NPBD, we identified
only one cytologic feature that was significantly useful,
namely, the presence of cell swirling within epithelial
groups in air-dried aspirates of PBD.15 The results of
our diagnostic accuracy in this study corroborates
those of others. Cytohistologic correlation was
achieved in 58% of NPBD, 47% of PBD, and 82% of
PBDA/DCIS cases. Only low and intermediate grade
DCIS were misclassified cytologically.
Other factors that may be hampering our ability to
accurately identify PBD cytologically is the heteroge-
37
NPBD %
present or
median score
PBD %
present or
median score
P valuea
1.5
1.5
12/51 (24%)
21/51 (41%)
6/51 (12%)
1.0
3.0
1.0
1.5
1.0
4/51 (8%)
1.5
1.0
1.0
1.5
2.0
17/32 (53%)
21/32 (66%)
10/32 (31%)
1.0
3.0
1.5
2.0
1.0
5/32 (16%)
2.0
1.0
1.0
0.0027b
0.003b
0.009
0.042
0.044
0.065
0.074
0.092
0.096
0.230
0.297
0.297
0.302
0.335
49/51 (96%)
2/51 (4%)
34/51 (67%)
47/52 (90%)
1/51 (2%)
0/52 (0%)
5/51 (10%)
45/51 (88%)
1/52 (2%)
29/32 (91%)
4/32 (13%)
24/32 (75%)
30/32 (94%)
0/32 (0%)
0/32 (0%)
3/32 (9%)
29/32 (91%)
0/32 (0%)
0.369
0.369
0.470
0.704
0.99
0.99
0.99
0.99
0.99
NPDB: non-proliferative breast disease; PBD: proliferative breast disease without atypia; PBDA: proliferative breast disease with atypia; DCIS: ductal carcinoma in situ.
a
Based on the Fisher exact test or Wilcoxon rank-sum test.
b
Statistically significant compared with the sequential rejective bonferroni procedure.
neity of changes within a given breast lesion. Foci of
DCIS are often accompanied by PBD and PBDA, and
proliferative breast disease may be present in a background of nonproliferative breast tissue; consequently, it is difficult to identify with certainty the
origin of the aspirated material. Cytohistologic correlation has also been hampered in previous studies by
the difficulty in determining the exact area within an
excisional biopsy from which an aspirate was derived.
The presence of needle tracts can be helpful, but they
are not always present. In an effort to eliminate much
of these sampling difficulties, we scraped specified
foci of excisional breast biopsies and correlated them
with the histologic sections prepared from the exact
areas that were scraped.
Smears of PBD and NPBD were similar in many
respects. Both typically exhibited cohesive cell groups
with mild nuclear overlap and few single cells, no or
mild nuclear pleomorphism, a nuclear size less than
three times the size of an RBC, and monolayers. Chromatin clumping and hyperchromasia were absent. Mi-
38
CANCER (CANCER CYTOPATHOLOGY) February 25, 2000 / Volume 90 / Number 1
FIGURE 1.
Nonproliferative breast disease is shown. (A) Ductal epithelial
cells are arranged in a monolayer with good cellular polarity and interspersed
myoepithelial cells (Diff-Quik stain, original magnification ⫻1000). (B) A monolayer of ductal epithelium with honeycomb arrangement, regular nuclei, and
fine, evenly distributed chromatin is shown (H & E, original magnification
⫻1000).
cronucleoli were often present. Less consistently,
smears of NPBD and PBD demonstrated a low to
moderate degree of cellularity. However, in standard
univariate analysis, we were able to identify six cytologic features that differed in NPBD and PBD. PBD
showed more complexity of epithelial groups, slitlike
lumenal spaces, a mixture of apocrine metaplastic
cells, nuclear pleomorphism, very large epithelial
groups/sheets, and cell swirling/streaming (as in our
previous analysis15) (Figs. 1 and 2). The latter feature
was the only one that was significant in both air-dried
and alcohol-fixed smears (Tables 3 and 4). However,
when the more conservative sequential rejective bonferroni procedure was used, only the degree of complexity and size of epithelial groups in the alcoholfixed preparations remained significant in distinguishing NPBD from PBD.
The different results observed for alcohol-fixed
and air-dried smears in the comparison of NPBD and
FIGURE 2. Proliferative breast disease without atypia is shown. (A) Cellular
smear showing large sheets of epithelial cells with complex architecture
(Diff-Quik stain, original magnification ⫻400). (B) This epithelial group illustrates a swirling pattern. The myoepithelial cells are evident (Diff-Quik stain,
original magnification ⫻1000).
PBD may have been a result, at least in part, of sampling. Even though the study design allowed precise
histologic correlation and greatly reduced sampling
error, it may not have eliminated it. NPDB and PBD
were often mixed in the histologic sections prepared
from the areas sampled. The amount of each epithelial
type and the sizes of the epithelial sheets resulting
from each smear of the same area may not have been
entirely consistent between the smear prepared for
alcohol fixation and the air-dried smear. Our data
suggest, however, that the architecture of epithelial
groups and sheets is better assessed in alcohol-fixed
smears. The spreading of cells that results from airdrying may result in flattening of the epithelial sheets,
making appreciation of architectural detail more difficult.
There were far more cytologic features that distinguished NPBD/PBD from DCIS/PBDA than distinguished NPBD from PBD. Seventeen of the 23 evaluated features showed significance in distinguishing
Cytology of Proliferative Breast Lesions/Frost et al.
FIGURE 3. Ductal carcinoma in situ, low grade, is shown. A cellular smear
shows two sheets of epithelial cells exhibiting mild nuclear enlargement and
pleomorphism as well as relatively abundant cytoplasm. The epithelial sheets
lack architectural complexity and exhibit some loss of cohesion at their
peripheries. Myoepithelial cells are absent in the sheet on the right (Diff-Quik
stain, original magnification ⫻400).
the NPBD/PBD group from DCIS/PBDA in air-dried
and/or alcohol-fixed smears (Tables 1 and 2). Eleven
features were significant in both preparations, including the presence of myoepithelial cells in the background, cellularity, cohesion, single cells, monolayers,
necrosis, nuclear enlargement, pleomorphism and
overlap, and nucleoli (micro vs. macro). Since hyperchromasia and chromatin clumping were evaluated in
alcohol-fixed smears only, their statistical significance
was only demonstrated in this preparation.
Smears of DCIS usually exhibited loss of cellular
cohesion with many single cells, large nuclear size
(greater than 3 times the size of an RBC) with moderate to marked overlap, and moderate to marked pleomorphism. The chromatin was clumped and hyperchromatic on alcohol-fixed smears. There was often a
background of necrosis. Less consistently, the smears
of DCIS were highly cellular. There was an absence of
myoepithelial cells within cell groups and in the smear
background, and an absence of cell streaming and
swirling (Fig. 3). Cytoplasmic vacuoles and macronucleoli were sometimes present. Only one case of
PBDA was included in this study. It demonstrated a
degree of nuclear overlap intermediate between
NPBD/PBD and DCIS, and the epithelial cells were
arranged in small groups.
Again, differences between alcohol-fixed and airdried smears in the comparison of NPBD/PBD and
DCIS/PBDA may have resulted from differences in
sampling between the two smears. However, the three
features that differed in significance between air-dried
smears and alcohol-fixed smears (i.e., cell swirling/
39
streaming, myoepithelial cells in epithelial groups,
and cytoplasmic vacuoles) were more often identified
in the alcohol-fixed smears than in air-dried smears,
suggesting the superiority of alcohol-fixed smears in
evaluating these features. The presence of necrosis in
some air-dried smears, but not alcohol-fixed smears,
prepared from NPBD/PBD likely results from the presence of necrosis-like material present in ectatic ducts.
This material is more likely to remain adherent to
air-dried than alcohol-fixed slides.
In order to minimize the sampling error, our study
design was based on direct scrapes of excisional breast
biopsies. There are few studies that assess the comparability of cytologic morphology in scrape preparations and FNA smears. In a recent comparison of
morphology in scrape preparations and FNAs, it was
demonstrated that scrape preparations yielded smears
with smaller clusters and more single cells and were
uniformly more cellular than FNA smears, but were
otherwise similar.22 These few differences must be
considered when applying the results of this study to
the interpretation of FNAs of the breast, but they do
not affect our comparison of NPD with PBD and
PBDA/DCIS, because only scrape preparations were
included for evaluation.
It is important for the cytopathologist to distinguish PBDA/DCIS from NPBD/PBD by FNA, because
the distinction carries management implications.
Rendering a cytologic diagnosis of PBDA/DCIS
prompts further workup, often a needle or open biopsy, to define better the type and extent of the lesion.
On the other hand, patients with a cytologic diagnosis
of benign NPBD or PBD may not require additional
workup. The clinical significance of distinguishing
NPBD from PBD is less dramatic; although women
with PBD have an approximately twofold greater risk
of developing invasive breast carcinoma than women
in the general population, further treatment is currently not indicated.17,23 However, the ability to identify women with PBD accurately, particularly when
these women also have a family history of breast carcinoma, by FNA may be potentially useful in identifying candidates for chemoprevention regimens, such
as tamoxifen, which has recently been demonstrated
to be effective in reducing the incidence of breast
carcinoma in high risk women by 49%.24
In conclusion, we have demonstrated that many
cytologic features allow a separation of DCIS from
NPBD/PBD. However, there are relatively few features
that reliably allow the distinction of PBD from NPBD.
Consequently, the identification of PBD cytologically
is limited.
40
CANCER (CANCER CYTOPATHOLOGY) February 25, 2000 / Volume 90 / Number 1
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