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and Ki-67 Expression
From the Departments of Cellular and MolecularPathology*
and PublicHealth,
University of Liverpool, Liverpool,United Kingdom
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Abstract |
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 Top Abstract Materials and MethodsResultsDiscussionReferences |
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(ER-) and Ki-67 using
morphometric image analysis as well as dual-labeled immunofluorescence
in HUT foci and in surrounding normal lobules of 25 patients that
progressed to breast cancer and 19 controls. Those patients that
progressed to breast cancer (cases) showed significantly higher ER-
[median, 57.00% of cells within individual HUT foci;
interquartile range (IQ), 33.48 to 67.78] and Ki-67
(median, 3.82%; IQ, 0.85 to 11.28) expression in their
HUT foci compared with controls (ER- median, 30.27%;
IQ, 19.75 to 52.50 and Ki-67 median, 0.77%;
IQ, 0.0458 to 1.72, P = 0.008 and
<0.001). No significant difference in expression of dual-stained cells
was found between cases and controls. Although normal lobules from
cases showed higher ER- expression compared with controls,
this was not statistically significant. Our data point to a previously
undescribed hormone-dependent pathway in this particular group of
breast neoplasms and suggest the possibility of selective hormonal
therapy to suppress the proliferative potential of these benign but
high-risk breast lesions. The findings of this study might have
important implications for improving breast cancer screening and
management strategies.
Epidemiological and experimental evidence suggest that breast cancer risk is related to the duration of estrogen exposure during puberty, the early postmenopausal period, and the menopausal period.3 Furthermore, the anti-estrogen tamoxifen decreases proliferation in breast cancer4 although its role in preventing the disease is at dispute at present.5 Estrogen is also associated with epithelial proliferation in noncancerous breasts during the menstrual cycle and in pregnancy.6,7 Hankinson and colleagues8 demonstrated a statistically significant positive association between the risk of breast cancer and circulating levels of estrogen providing a strong evidence of causal relationship between postmenopausal estrogen levels and the risk of breast cancer.
It has been suggested that estrogen receptor (ER)- positivity in
benign breast epithelium could be a risk factor for breast
malignancy9
because the presence of ER- is thought to
render cells susceptible to proliferation stimulus of estrogens. The
median of the percentage of ER--positive cells was higher in
Australian postmenopausal females when compared with the Japanese.
These data are compatible with the hypothesis that expression of ERs in
normal breast tissues increases the risk of breast cancer, and provides
an explanation for the poor international concordance between breast
cancer occurrence and estrogen production rates or blood
concentrations.10
Several other studies have shown a very tight association between Ki-67
immunoreactivity and the cell cycle, with expression beginning in the
mid to late G1, rising through S phase and
G2 to reach maximum in mitosis.11,12
Clarke and colleagues13
described almost mutual exclusion
of steroid receptor expression and cell proliferation as evidenced by
the lack of dual immunostaining for ER- and Ki-67 antigen.
Previous work in this laboratory revealed dysregulation of ER-positive
proliferating cells, increasing from normal lobules through hyperplasia
to in situ and invasive breast cancer.14
These
findings were followed by identification of heterogeneity in ER- and
proliferation in non-atypical hyperplasia.15
Although
those two studies showed some interesting observations, no clinical
outcome data were available. We have now identified a significant
number of ductal proliferative lesions representing a step of
progression toward the development of breast carcinomas mixed with
morphologically similar lesions of age and date of biopsy matched
controls. We have studied the relationship between ER- status and
cellular proliferation in this cohort of hyperplastic epithelial breast
lesions with known clinical outcome in an attempt to verify the
putative role of this interaction in the process of breast
carcinogenesis.
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Materials and Methods |
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TopAbstractMaterials and MethodsResultsDiscussionReferences |
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We designed a case-control study using histological specimens
collected between the beginning of January 1979 and the end of January
1999 from patients in the Merseyside and Cheshire area, UK. Those
comprised patients who underwent biopsy revealing benign diagnoses at
three hospitals (The Royal Liverpool University Hospital, Broadgreen
Hospital, and Lourdes Hospital). Included as study cases, were all
patients with a benign breast lesion followed by in situ or
invasive cancer of either breast at least 6 months after the benign
lesion. Each study case was matched for age and date of biopsy with
three controls that had histories of benign breast lesions only. When a
patient had more than one benign specimen, then all specimens were
examined. The study has been conducted on 674 biopsy specimens from 502
patients including 120 benign biopsies from patients who subsequently
developed breast cancer and 382 controls that were not known to develop
breast cancer spanning a 20-year follow-up period (Table 1)
. Excluded from the study cases and
controls were all patients with axillary fat, scars from previous
mastectomies, breast skin- and lymph node-only specimens, in
situ or invasive breast cancer before the benign diagnosis in
either breast, in situ or invasive breast cancer in either
breast less than 6 months after the benign breast lesion, and patients
who had another cancer before breast cancer.
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Immunostaining Procedure
Slides and blocks from patients with HUT were selected and
reviewed. From the 117 patients in which HUT was identified
morphologically, staining was performed on 44 patients that comprised
25 that progressed to breast cancer and 19 controls (Table 2)
. ER- was detected with a mouse
monoclonal anti-ER- antibody (clone 1D5; DAKO Ltd., Ely, Cambridge,
UK) and Ki-67 with a rabbit polyclonal anti-Ki-67 antibody (Novocastra,
Newcastle-on-Tyne, UK). Adjacent morphologically normal lobules were
also stained. Immunostaining was performed using a standard
streptavidin-biotin method with previous pressure cooking for antigen
unmasking. Negative controls in which the primary antibody was omitted
and three positive controls of ER-positive breast carcinoma of varying
staining intensities were included in each batch of immunostaining. The
method was identical to that used for routine assessment of ER and
Ki-67 status in which the laboratory performs well in the UK External
Quality Assessment Scheme. Also stained were 21 malignant breast tumors
that developed after benign diagnoses of HUT using the identical
anti-ER- monoclonal antibody and staining procedure.
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This was performed as previously described15 by the application of 100 µl of a mixture of both primary antibodies (diluted appropriately in 5% bovine serum albumin/Tris-buffered saline) for 80 minutes. The dilution used for the monoclonal ER antibody 1D5 (DAKO) was 1:30 and for the monoclonal rabbit anti-human Ki-67antibody (Novocastra) was 1:100. This was followed by the application of 100 µl of a mixture of both secondary antibodies diluted in 5% bovine serum albumin/Tris-buffered saline for 30 minutes. The secondary antibodies used were tetramethylrhodamine B isothiocyanate-conjugated swine anti-rabbit antibody 1:50 (DAKO) and biotinylated sheep anti-mouse antibody 1:100 (Amersham Life Sciences, UK). The slides were then incubated with fluorescein-avidin conjugate 1:100 (diluted in 5% bovine serum albumin/Tris-buffered saline) for 30 minutes to visualize the anti-mouse antibody. All incubations were at room temperature and washes in phosphate-buffered saline were performed in between. The slides were then coverslipped and mounted using an anti-fading medium containing 4',6-diaminido-2-phenylindole (Vectashield; Vector Laboratories, UK) to stain DNA.
Assessment of Immunostaining
To maximize consistency of scoring, only nuclei showing moderate
or strong staining were regarded as positive. Ductal proliferations
were assessed for the percentage of ER-(+) and Ki-67(+) cells within
lesions using a Leica KS-300 image analysis system. Each focus of HUT
was identified within both cases and controls according to the criteria
of the UK Breast Screening Program.16
Every image was
automatically digitized before analysis using a custom-designed program
that detected the nuclear diaminobenzidine reaction product as
well as unstained nuclei. Before counting, each field was masked to
remove from the analysis all elements (eg, adjacent normal tissues)
that were not components of the HUT. The area of the resulting unmasked
field was calculated automatically so that all numerical counts were
thereafter generated with respect to unit area of HUT foci. The
analysis yielded two sets of data that included both stained and
unstained cells for each selected focus. All epithelial cells present
within every focus and all HUT foci for each patient were examined. The
percentage of positive cells was calculated as a proportion of total
number of cells present in each HUT focus. The percentage of ER(+) and
Ki-67(+) cells was then averaged for each patient. Stromal cells,
myoepithelial cells, and macrophages remaining within the unmasked
fields were not included in this analysis. Contiguous ER staining was
also assessed as defined by the criterion of 10 or more ER(+) cells in
contact with each other. ER positivity was defined using a 10% cutoff
conventionally used as the median value of its expression in each
patient.17
As internal controls for each patient,
identical criteria were applied to the adjacent but microscopically
normal nonatrophic lobules to assess whether dysregulation of both
markers occurred in normal lobules.
Assessment of Fluorochrome-Labeled Staining
Each field was examined under high power for the red (tetramethylrhodamine B isothiocyanate), green (fluorescein), and blue (4',6-diaminido-2-phenylindole) fluorochromes, using appropriate filters (Zeiss filters 15, 10, and 2, respectively) to assess the presence or absence of dual-labeled cells. The percentage of dual-expressing cells was calculated in relation to total cell number within hyperplastic foci and adjacent normal lobules.
Statistics
Possible association between each benign lesion, including HUT and subsequent malignant transformation, was measured by Pearson’s chi-square test (without continuity correction) and calculated with Minitab for Windows, version 12. The relative risk and its 95% confidence interval (CI) for this lesion and for the ER-rich and proliferative HUT foci as well as the odds ratio were calculated with the StatCalc program within EpiInfo version 618 using a 10% cutoff point for ER positivity.17 Foci positive for Ki-67 included all those containing figures more than zero. For all calculations, the median values of expression were used for both the HUT foci and for normal lobules. The data from immunohistochemistry and immunofluorescence were analyzed by the nonparametric two-sided Mann-Whitney test, Spearman’s rank-correlation coefficient (rs), and multiple logistic regression analysis (taking a predicted probability of P = 0.5 as cutoff point in classification tables) using SPSS for Windows (version 10). For comparing ER status in HUT and subsequent malignant tumors, a paired t-test (confirmed by a paired Wilcoxon test) was used.
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Results |
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TopAbstractMaterials and MethodsResultsDiscussionReferences |
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; Pearson’s chi-square test,
P = 0.01). The relative risk and the odds ratio of
developing breast cancer after a benign biopsy that included HUT were
respectively 1.53 (CI, 1.10 to 2.13) and 1.78 (CI, 1.10 to 2.88). The
mean age of the patients analyzed immunohistochemically was 50.66
years. The mean age for the cases that progressed to breast cancer was
52.53 years (range, 35.52 to 69.77 years) whereas that of the controls
was 48.05 years (range, 38.60 to 59.42 years). The average number of
cells examined in each focus of HUT was 546.23 (range, 66 to 3974
cells).
ER- Expression in Normal Lobules
A total of 63 morphologically normal lobules with premenopausal
appearance from 43 patients examined for ER- positivity comprised 41
from patients who subsequently developed breast cancer and 22 from
matched controls. The mean number of normal lobules examined for each
patient was 1.68 (range, 1 to 5 lobules). The majority of cells were
unstained for ER-, but with a few interspersed ER-(+) cells
(Figure 1A)
. The median percentage of
ER-(+) cells was 28.22 [interquartile range (IQ): 12.18 to 45.98]
in the cases that progressed to breast cancer and 20.1 (IQ, 8.9 to
46.68) in the controls. This difference was not statistically
significant (Mann-Whitney, P = 0.35).
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(+) Cells in HUT
The mean number of HUT foci examined for each patient was 2.98
(range, 1 to 9 foci). Examination of 131 foci of HUT from 44 patients
confirmed the expression of ER-(+) cells in HUT foci from patients
who subsequently developed breast cancer (Figure 1B)
to be higher
(median, 57.0%; IQ, 33.48 to 67.78) when compared with those from
controls (median, 30.27%; IQ, 19.75 to 52.50). This was highly
significant (Mann-Whitney, P = 0.008; Table 2
and
Figure 2A
). Some HUT foci exhibited
contiguous ER-(+) staining of 10 or more ER+ in contact to each
other. Contiguous ER staining correlated significantly with the
percentage of ER-expressing cells irrespective of whether the specimen
was a case or a control (rs = 0.44,P < 0.001). Using a 30% cutoff for ER-
positivity, most HUT foci (85.7%) showed contiguous staining. With a
60% cutoff for ER positivity, all hyperplastic foci showed contiguous
staining.
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expression in normal lobules and HUT foci, the
percentage of positively stained cells was higher in HUT foci than in
the surrounding normal lobules for those cases that progressed to
cancer and for the controls. The difference was higher in biopsies from
the cases that subsequently progressed (P =
0.02) although that of the controls was not statistically significant
(P = 0.21; Table 3
).
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Expression in Carcinomas
Of the 21 breast carcinomas that were available within the archive
for analysis, (Table 4)
11 were invasive ductal carcinomas
(NST), 18 (85.7%) were ER-(+) and 3 (14.3%) were
ER-(-). All three ER-(-) tumors
occurred in patients who had previously demonstrated ER- positivity
in their HUT foci. A significant correlation was found between mean
ER- expression in HUT and that of cancer
(rs = 0.459, P =
0.036). A paired t-test (confirmed by a Wilcoxon test)
showed that the mean shift between benign and malignant values is
significantly different from zero (P = 0.047).
The mean proportion of the ER-(+) cells for the cancer that
subsequently developed from HUT was 68.3%.
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The percentage of Ki-67(+) cells was similar (median, 0.7%) in
the morphologically normal lobules within the cases and controls (Table 3
and Figure 1C
).
Percentage of Ki-67(+) Cells in HUT Foci
Eighty-seven HUT foci were examined for Ki-67 expression by
morphometric analysis in both groups of patients. The percentage of
proliferating cells was significantly higher (median, 3.82%; IQ, 0.85
to 11.28) in the cases (Figure 1D)
compared with controls (median,
0.77%; IQ, 0.0458 to 1.72). However, the proliferation data for the
HUT foci of the controls were almost identical to the data obtained
from normal lobules. The high expression of Ki-67 in HUT foci in cases
that progressed to cancer when compared with the controls was
statistically highly significant (Mann-Whitney, P <
0.001; Table 2
and Figure 2B
). Ki-67(+) cells were mainly peripheral
and discrete.
The median percentage of Ki-67(+) cells in HUT and normal foci from the
cases that progressed to cancer and their controls was compared.
Significantly higher Ki-67 expression was found in HUT that progressed
to cancer when compared with its surrounding lobules
(P = 0.004). However, controls showed no
significant difference (P = 0.92; Table 3
).
Relation of ER and Ki-67 Expression in HUT Foci to Breast Cancer Risk
The odds ratio of ER expression (using a 10% cutoff) in HUT foci for those cases that developed breast cancer versus the controls was 3.06 (CI, 0.49 to 18.88). Expression of Ki-67 in HUT, for all positive values, for those cases that progressed versus the controls yielded an odds ratio of 1.62 (CI, 0.33 to 7.78). The age-adjusted odds ratio for ER was 2.28 (CI, 0.727 to 7.16) whereas that for Ki-67 was 1.47 (CI, 0.458 to 4.769). However, neither was statistically significant. Logistic regression analysis, using both markers in a predictive model for developing breast cancer, identified the overall correct classification rate of both ER and Ki-67 in HUT to be 67.4% with a positive predictive value of 72.2% and negative predictive value of 64.3%.
Dual-Expression Cells in Normal and Hyperplastic Foci
Cells co-expressing ER- and Ki-67 were found in 5.1% and
13.5% of normal lobules and HUT foci, respectively (Figure 1, E and F)
. Of the latter, 60% were cases that progressed whereas 40% were
controls. The median expression of dual-stained cells in HUT foci was
0.0955% epithelial cells in the cases that progressed to cancer and
0.0527% epithelial cells in the controls. This difference was not
statistically significant (Mann-Whitney test, P = 0.9).
For normal lobules, the median percentage of dual-expressing cells was
0.0460% epithelial cells in those cases that progressed to cancer and
0.010% epithelial cells in the controls. This also was not significant
(P = 0.56). Even the presence or absence of dual
staining was not statistically different between the two groups.
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Discussion |
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TopAbstractMaterials and MethodsResultsDiscussionReferences |
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Evidence from recent studies indicates that HUT is a
heterogeneous entity containing subgroups identified according to the
criterion of ER-(+) proliferating cells.15
Although,
the level of risk after a benign biopsy containing HUT can be
determined in a population-based group, we are still unable to predict
it on individual basis, because morphological high-risk subtypes of HUT
have not been identified. Further progress is likely to depend on
delineating the molecular events that define these lesions. In an
elegant study, Gobbi and colleagues24
showed an
association between breast cancer risk and the expression pattern of
transforming growth factor-ß-RII in HUT.
Through a nested case-control study, we have now confirmed a striking
increase in both ER- and Ki-67 expression in proliferative foci from
those patients who progressed to breast cancer. In the present series,
the odds ratio of developing breast cancer after a diagnosis of HUT in
otherwise benign breast biopsies was 1.78 (CI, 1.10 to 2.88). The odds
ratio of developing breast cancer in association with ER-positive HUT
was increased to 3.06 (CI, 0.49 to 18.88). However, this was not
statistically significant. When ER and Ki-67 are considered together in
a logistic regression model, the overall predictive value of both
markers for correctly classifying the cases that progressed to breast
cancer and the controls was 67.4%. Because age, follow-up period, and
geographical factors were each controlled in this study, these findings
reflect a genuine increase in the expression of ER- and Ki-67 in a
high-risk subset of non-atypical lesions. Although the morphological
appearance of HUT from cases and controls were histologically
identical, they showed differences in hormone receptor and
proliferation marker expression, which might have contributed to
different biological behavior. All three ER-(-) tumors were found
in patients who had previously demonstrated ER- positivity in their
HUT foci. With respect to individual patients, expression of ER in
normal lobules and in HUT foci is likely to be influenced by a number
of different variable factors that include age, family history, time in
the menstrual cycle, and menopausal status. Although these latter
pieces of information are unavailable in this present series, and would
be valuable to include in any prospective study, there are no published
data to suggest that ER expression in HUT is influenced by the phase of
the cycle or menopausal status.
The process of ER activation stimulates DNA synthesis, cell division,
and the production of biologically active proteins that include pS2,
transforming growth factor-, and epidermal growth factor that
influence cell growth and differentiation. Exposure to estrogen may
contribute to mammary carcinogenesis by stimulating proliferation of a
clone of precancerous cells or by increasing the chance of spontaneous
mutations. Alternatively, estrogen could decrease cell-cycle transit
time so that a spontaneous mutation becomes fixed before repair. An
additional probability is that estrogen may have a direct genotoxic
effect.25
Our findings support the hypothesis that hormonal stimuli that induce
growth and differentiation in the normal breast also contribute to the
development of mammary malignancy and that the initial steps along the
mammary carcinogenic pathway are estrogen-dependent. This mechanism
might apply to ER-(+) as well as ER-(-) cancers. Increased
expression of ER- in premalignant lesions of those patients who
developed breast cancer may lead to increased sensitivity of the target
tissue to the effect of circulating estrogens that, in turn, could
stimulate proliferation of the hyperplastic mammary epithelial cells.
The increasing number of mitotic events would thus provide
opportunities for genetic instability and initiation of malignancy
during cell division.
In conclusion, we have demonstrated the existence of a positive
association between ER- and cellular proliferation in a subset of
ductal hyperplasia that definitely progressed to breast cancer.
According to our results, the increased expression of both ER- and
Ki-67, although not necessarily their simultaneous dual expression by
individual cells, might define a subset of hyperplastic lesions with an
increased risk of subsequent breast cancer development. This group
could be selected for prophylactic anti-estrogen therapy to diminish
the proliferative activity of those benign but high-risk lesions.
Recently, Visscher and colleagues26
showed that the
anti-estrogen, tamoxifen, selectively inhibits the appearance or growth
of preinvasive lesions in a xenograft model of early human breast
cancer. These findings could have important implications for
pathological diagnosis and assessment of breast cancer risk.
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Acknowledgements |
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Footnotes |
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Support for this study was provided by the Research and Development Office of the Royal Liverpool and Broadgreen University Hospitals (NHS) Trust.
Accepted for publication November 1, 2001.
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References |
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TopAbstractMaterials and MethodsResultsDiscussionReferences |
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