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2083
Estrogen Receptor Status, Determined by
Immunohistochemistry, as a Predictor of the
Recurrence of Stage I Endometrial Carcinoma
Paola A. Gehrig, M.D.1
Linda Van Le, M.D.1
Babatunde Olatidoye,
Joseph Geradts, M.D.2
BACKGROUND. The aim of this study was to compare the concordance between
2
M.D.
1
Division of Gynecologic Oncology, Department of
Obstetrics and Gynecology, University of North
Carolina, Chapel Hill, North Carolina.
2
Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill,
Chapel Hill, North Carolina.
Presented in part at the Society of Gynecologic
Investigators meeting, Atlanta, Georgia, March 11–
14, 1999.
Dr. Olatidoye’s current address: Department of
Pathology, Box 3712 Duke University Medical Center, Durham, NC 27710.
Dr. Geradts’ current address: Nuffield Department
of Pathology and Bacteriology, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DU,
United Kingdom.
Address for reprints: Linda Van Le, M.D., Division
of Gynecologic Oncology, CB 7570 MacNider
Building, University of North Carolina, Chapel Hill,
NC 27599.
Received March 1, 1999; revision received June
28, 1999; accepted June 28, 1999.
© 1999 American Cancer Society
immunohistochemical (IHC) and biochemical (RIA) methods for determining hormone receptor status in patients with endometrial carcinoma and to determine
whether IHC expression of estrogen and progesterone receptors (ER and PR) has
prognostic significance.
METHODS. Paraffin blocks were obtained from patients diagnosed with endometrial carcinoma between 1987 and 1991. IHC analysis for ER and PR expression was
performed and scored based on staining intensity and the percentage of tumor
cells with nuclear staining. Biochemical assays were performed on frozen tissues.
Concordance between the two methods was evaluated and hormone receptor
status was correlated with tumor grade, stage, recurrence and survival.
RESULTS. ER and PR expression, determined by IHC, correlated well with RIA levels
(Spearmans correlation coefficient, P 5 0.006 and 0.0005, respectively). Determination of ER and PR expression by both methods was correlated with tumor grade.
Hazards ratios revealed that the absence of ER and PR expression, determined by
both IHC and RIA, independently correlated with recurrence in early stage disease
(P , 0.05).
CONCLUSIONS. Historically, receptors have been determined by RIA. In this study,
IHC and RIA were equally suitable for determination of ER and PR. This is
significant clinically as IHC has several advantages over RIA, including easier
processing, lower cost, greater speed, and applicability to fixed tissue samples. In
addition, ER negative status was predictive of the recurrence of Stage I tumors
independent of tumor grade. ER status may aid the clinician in planning treatment
when adjuvant treatment is controversial. Cancer 1999;86:2083–9.
© 1999 American Cancer Society.
KEYWORDS: endometrial carcinoma, estrogen receptors, progesterone receptors,
immunohistochemistry.
E
ndometrial carcinoma is the most common gynecologic malignancy, accounting for 6% of all new cancer cases, with approximately 36,000 new cases diagnosed in the United States in 1997.
Although endometrial carcinoma accounts for only 2% of all cancerrelated deaths, the number of women dying of this disease (4900 per
year) still is significant.1
Although endometrial carcinoma has relatively good cure rates,
86% in Caucasians and 55% in African-Americans, there is motivation
to determine which prognostic factors correlate with patient outcome. Well-described prognostic factors include stage of disease at
the time of diagnosis, histologic type, degree of tumor differentiation,
depth of myometrial invasion, and lymphovascular space invasion.
2084
CANCER November 15, 1999 / Volume 86 / Number 10
Although the importance of hormone receptors in
the management of breast carcinoma patients is well
established,2 the clinical significance of hormone receptor expression in endometrial carcinoma is less
clear. Estrogen receptor (ER) status is believed to provide prognostic information independent of tumor
stage and grade in women with endometrial carcinoma.3– 6 However, progesterone receptor (PR), and
not ER, is suggested to be more predictive of disease
free survival.6 –11
The methods by which hormone receptor status
in patients with endometrial carcinoma have been
evaluated are immunohistochemistry (IHC)4,5,10,12,13
and radioimmunoassay (RIA);6 –9,11,14 IHC has a benefit over RIA, in that hormone receptor status can be
determined for archival tissues in contrast to RIA,
which must be performed on tissues before histologic
processing occurs. IHC has other advantages over RIA,
including easier tissue handling, greater speed, lower
cost, and wider availability. Several authors have
shown that IHC can be as sensitive and specific as
RIA;4,15–20 however, few have made the correlation
between IHC methodology and disease free interval
and survival.4,5,10 In addition, until recently, RIA was
the preferred method for determining ER and PR status in gynecologic specimens. We therefore undertook
this study to determine the concordance between IHC
and RIA determination of hormone receptor status
and the prognostic significance and clinical applicability of ER and PR status in patients with endometrial
carcinoma as determined by IHC.
MATERIALS AND METHODS
Patients
Of the surgically staged patients with endometrial carcinoma who were treated at the University of North
Carolina Hospitals between 1987 and 1991, 72 patients
were evaluated for the presence of estrogen and progesterone receptors. The patients were 72 consecutive
cases in whom the attending physician requested receptor status by RIA. The 72 patient charts were reviewed for disease stage at the time of initial surgery,
histologic tumor grade, and cell type in accordance
with the International Federation of Gynecology and
Obstetrics (FIGO) criteria. Those patients who were
staged surgically before 1988 were reclassified according to the 1988 FIGO criteria. Charts also were reviewed for disease free interval, location of tumor
recurrence, and survival. This study met the exemption criteria set forth by the Institutional Review Board
at the University of North Carolina.
RIA
RIA analysis was performed by the SmithKline
Beecham clinical laboratories. The method used was a
dextran-coated, charcoal-scatchard analysis with tritium.
Materials
Monoclonal anti-ER antibody 1D5 was purchased
from Dako Corporation (Carpinteria, CA). Monoclonal
anti-PR antibody 1A6 was obtained from Novocastra
via Vector Laboratories (Burlingame, CA). The secondary detection reagents, Elite ABC kit, were from Vector
Laboratories.
IHC
The immunostains were performed on an automated
stainer (Biotek 2000; Ventana Systems, Phoenix, AZ).
The primary incubation time for both assays was 30
minutes after antigen retrieval in 0.01 M citrate buffer
(20 minutes at 95–100°C). Anti-ER antibody 1D5 was
used at a dilution of 1:20, and anti-PR antibody 1A6
was used at a dilution of 1:15. The detection reaction
used the Vector Elite ABC kit (manufacturer-recommended protocol). Diaminobenzidine and hematoxylin counterstains were used for color development.
Interpretation
Although RIA was performed for 72 patients, only 67
tumors were evaluable for ER and PR by IHC. The two
study pathologists (J. G. and B. A. O.), blindly and
independently, evaluated hormone receptor expression by IHC. The average nuclear staining intensity
was graded as 0 (absent), 1 (weak), 2 (moderate), and
3 (strong). The percentage of tumor cells with positive
nuclear staining also was estimated. The immunohistochemical score was determined by multiplying the
average staining intensity by the percentage of tumor
cells stained.16 Thus, the theoretical range of scores
was from 0 to 300. Significant differences in interpretation (for example, negative vs. positive or low positive vs. high positive scores) were resolved in conference. However, such differences in opinion only
occurred in a very small subset of cases. In all other
cases, the two observer scores were averaged. In preliminary analysis, the best agreement between IHC
analysis and RIA analysis with regard to separating
negative cases from positive cases was found when the
cut-off values were set at an IHC score of 20 and an
RIA value of 50 fmol/mg protein (ER, correlation coefficient [r] 5 0.63; PR, r 5 0.67).
Statistical Analysis
The correlations between tumor grade, disease stage,
and ER and PR status, determined by IHC and RIA,
ER Predicts Endometrial Carcinoma Recurrence/Gehrig et al.
2085
FIGURE 2. Concordant and discordant expression of hormone receptors by
FIGURE 1.
The American Joint Committee on Cancer (AJCC) Staging for
Endometrial Carcinoma.
were calculated using both the Kruskal–Wallis test and
the Fisher exact test. Because the correlations were
not linear, the degree of correlation between the IHC
and RIA measures for both ER and PR was evaluated
using Spearmans correlation coefficient. Finally, Cox
proportional hazards regression models were used to
evaluate the ability of ER and PR (with both IHC and
RIA) to predict the time to disease recurrence and the
time to death. Three models were used for the Cox
proportional hazards regression: The first model included only ER and PR as variables, the second model
included both ER and PR variables as well as a variable
for grade, and the third model included a variable for
disease stage and tumor grade in addition to the ER
and PR variables.
RESULTS
Although biochemical receptor data were available for
72 patients, complete clinical data, including follow-up and IHC score, were available for only 55 patients. Because one of the main objectives was to
compare the prognostic value of RIA hormone receptor levels with IHC ER and PR status, analysis was
restricted to the 55 patients with complete data.
Among the 17 patients who were excluded, 10 had
Stage I disease, 4 had Stage II disease, and 3 had Stage
III or IV disease, as determined by the American Joint
Committee on Cancer staging system (Fig. 1). Of the
17 excluded patients, 2 are alive with disease, and 2
others are dead. Among the 55 patients who were
evaluated, 36 patients had surgical Stage I disease
(65.5%), 8 had Stage II disease (14.5%), and 11 had
Stage III–IV disease (20%). When the patients were
divided according to histologic tumor grade, 13 had
radioimmunoassay (RIA) and immunohistochemistry (IHC). Concordant expression: (A) Strongly positive progesterone receptor (PR) staining of Grade 1
carcinoma (IHC score, 292; RIA value, 2827 fmol/mg). (B) Negative PR staining
of Grade 3 carcinoma (IHC score, ,20; RIA value, 13 fmol/mg). Note the
distinct staining of the nonneoplastic epithelium. Discordant expression: (C)
Strongly positive estrogen receptor (ER) stain of Grade 1 carcinoma (IHC score,
285; RIA value, 0 fmol/mg). (D) Negative PR stain of Grade 3 carcinoma (IHC
score, ,20; RIA value, 120 fmol/mg). Note the distinct staining in the admixed
stroma. Original magnification, 3200 in A and C, 3400 in B and D.
Grade 1 tumors (23.6%), 24 had Grade 2 tumors
(43.6%), and 18 had Grade 3 tumors (32.8%).
The IHC score was determined by multiplying the
average nuclear staining intensity for ER and PR with
the percentage of tumor cells stained16 (Fig. 2). Of the
55 tumors evaluated by IHC, 48 tumors (87.3%) were
ER positive, 42 tumors (76.4%) were PR positive, 42
tumors (76.4%) were ER positive and PR positive, 6
tumors (10.9%) were ER positive and PR negative, 0
tumors were ER negative and PR positive, and 7 tumors (12.7%) were ER negative and PR negative. Of the
55 tumors evaluated by RIA, 32 tumors (58.2%) were
ER positive, 42 tumors (76.4%) were PR positive, 30
tumors (54.6%) were ER positive and PR positive, 2
tumors (3.6%) were ER positive and PR negative, 12
tumors (21.8%) were ER negative and PR positive, and
11 tumors (20%) were ER negative and PR negative.
Examples of concordance between IHC and RIA expression of hormone receptors are shown in Figure
2A,B, and discordant cases are shown in Figure 2C,D.
Intratumor receptor heterogeneity, in which expression was found in some areas of malignant epithelium
but not in others, also was encountered and is exemplified in Figure 3. It is noteworthy that the RIA
PR level of this tumor was elevated markedly at 201
fmol/mg.
To determine whether hormone receptor expression by RIA correlated with expression by IHC, kappa
statistics for both ER and PR were calculated using RIA
2086
CANCER November 15, 1999 / Volume 86 / Number 10
TABLE 2
Agreement of Progesterone Receptor Positivity and Negativity
Determined by Immunohistochemistry and Radioimmunoassay
IHCa
RIAb
Negative
Positive
Negative
Positive
11
2
2
40
IHC: immunohistochemistry; RIA: radioimmunoassay.
a
Negative IHC, score ,20; positive IHC, score .20.
b
Negative RIA, ,50 fmol/mg protein; positive RIA, .50 fmol/mg protein.
c
P 5 0.0005.
FIGURE 3. Intratumor receptor heterogeneity shown in PR staining of a Grade
3 adenocarcinoma: The RIA level for this tumor was 201 fmol/mg. Note the
positive staining in the area of the tumor on the right (arrow) and the complete
negativity in the tumor on the left. In addition, nonneoplastic glands also
stained strongly (arrowhead).
TABLE 1
Agreement of Estrogen Receptor Positivity and Negativity by
Immunohistochemistry and Radioimmunoassay
IHCa
RIAb
Negative
Positive
Negative
Positive
6
1
17
31
IHC: immunohistochemistry; RIA: radioimmunoassay.
a
Negative IHC, score ,20; positive IHC, score .20.
b
Negative RIA, ,50 fmol/mg protein; positive RIA, .50 fmol/mg protein.
c
P 5 0.006.
and IHC dichotomies, in which tumors were categorized as either positive or negative based on previously
determined cut-off points. The concordance between
IHC and RIA analysis for both ER (Table 1) and PR
(Table 2) was statistically significant using this
method. The actual RIA and IHC values for ER and PR
also were correlated significantly (data not shown)
with P 5 0.0005. However, as evidenced by Spearmans
correlation coefficients, the PR correlation (0.75) between methods was considerably stronger than the ER
correlation (0.52).
Correlations between hormone receptors, tumor
grade and disease stage were determined using the
Kruskal–Wallis test; the medians for both ER measures
and PR measures were related to disease stage and
tumor grade. The median values of both ER measures
and PR measures show a linear correlation with tumor
grade when patients were separated into groups ac-
cording to low-grade and high-grade disease. In all
patients, the higher the grade, the lower the ER and PR
values (Fig. 4A,B). Although the trend for ER was not
statistically significant, there was a steady decrease in
median values with increasing tumor grade. The median values for ER and PR did not show a consistent
correlation with disease stage (Fig. 4C,D). Only the ER
measure (IHC) showed a consistent, although not statistically significant, trend in relation to disease stage.
The median follow-up was 59 months for both
recurrences and death. There were 12 patients who
had disease recurrences (21.8%), with a median time
to recurrence of 11 months, and 4 patients died (7%),
with a median time to death of 18 months. It is noteworthy that 7 of the recurrences and 3 of the deaths
occurred among the patients with Stage I disease. The
Cox proportional hazards regression model was used
to evaluate the ability of ER and PR, determined by
either IHC or RIA, to predict the time to recurrence
(Tables 3, 4) and the time to death. The hazards ratios
for disease recurrence (Table 3) for ER among all patients all were .1.0, with the “null” hazard set at 1.0.
However, when adjusted for advanced stage disease,
there was a significant risk if the ER status by IHC was
negative (HR 5 5.2; P 5 0.03). When all patients were
considered, the hazards correlating PR and tumor
grade were elevated, although none reached significance. To further evaluate deaths occurring in patients
with Stage I disease, the regression models were applied to these patients in a separate analysis (Table 4).
When considering ER status, all hazards ratios were
elevated significantly, with the ratios for IHC (P 5
0.01) slightly higher than the ratios for RIA (P 5 0.04).
In Stage I patients, the hazards ratios of recurrence for
PR, when performed by RIA, were elevated significantly for RIA alone and for RIA adjusted for tumor
grade (P 5 0.01 and P 5 0.02, respectively). Ratios
were elevated, but not significantly, for PR by IHC in
Stage I patients. Therefore, when controlling for tumor
ER Predicts Endometrial Carcinoma Recurrence/Gehrig et al.
2087
FIGURE 4.
Median ER and PR values, as
determined by RIA (fmol/mg protein) and IHC
score by tumor grade (A,B) and disease stage
(C,D). (A) ER (RIA), P 5 0.03; PR (RIA), P 5
0.0009. (B) ER (IHC), P 5 0.10; PR (IHC), P 5
0.02. (C) ER (RIA), P 5 0.29; PR (RIA), P 5 0.62.
(D) ER (IHC), P 5 0.09; PR (IHC), P 5 0.15.
TABLE 3
Disease Recurrence Hazard Ratios and 95% Confidence Intervals for
Estrogen Receptor and Progesterone Receptor, as Measured by
Radioimmunoassay and Immunohistochemistry, Alone and Adjusted
for Tumor Grade and Disease Stage
TABLE 4
Disease Recurrence Hazard Ratios and 95% Confidence Intervals for
Estrogen Receptor and Progesterone Receptor, as Measured by
Radioimmunoassay and Immunohistochemistry, for Stage I Patients
Alone and Adjusted for Tumor Grade
All stages (95% CI)
Adjust for
ER
Nothing
Grade 3
Stages III–IV
PR
Nothing
Grade 3
Stages III–IV
All stages (95% CI)
RIA (<50)
IHC (<20)
2.2 (0.7–6.9)
1.8 (0.6–5.9)
1.6 (0.5–5.3)
2.8 (0.8–10.3)
1.9 (0.5–7.7)
5.2 (1.2–2.3)a
2.8 (0.9–8.8)
1.7 (0.4–6.8)
2.4 (0.7–7.6)
2.0 (0.6–6.7)
1.1 (0.3–4.4)
1.7 (0.5–5.7)
95% CI: 95% confidence interval; RIA: radioimmunoassay; IHC: immunohistochemistry; ER: estrogen
receptor; PR: progesterone receptor.
a
Significant hazard ratios.
grade, negative ER status by RIA and IHC was found to
correlate with increased disease recurrence in Stage I
patients. In contrast, only negative PR status by RIA,
and not by IHC, was found to correlate with disease
recurrence in Stage I patients.
The correlation between the 4 deaths and hormone receptor status also was evaluated; however, the
hazards ratios were unstable, with very large 95% confidence intervals for this small number of patients
(data not shown). Overall, patients with low ER and PR
values by both RIA and IHC were at an increased risk
Adjust for
ER
Nothing
Grade 3
PR
Nothing
Grade 3
RIA (<50)
IHC (<20)
5.7 (1.1–30)a
5.5 (1.1–29)a
8.1 (1.8–37)a
7.6 (1.6–36)a
7.7 (1.5–32)a
7.6 (1.5–40)a
4.2 (0.9–19)
4.1 (0.7–22)
95% CI: 95% confidence interval; RIA: radioimmunoassay; IHC: immunohistochemistry; ER: estrogen
receptor; PR: progesterone receptor.
a
Significant hazard ratios.
of death. Because of the small number of deaths in this
series, statistical significance could not be reached.
DISCUSSION
Several studies have evaluated ER and PR status in
patients with endometrial carcinoma.3–11,14 –19 The
majority of these studies were performed using biochemical methods, such as RIA on frozen tissues.6 –9,11,14
A recent trend has been to evaluate ER and PR status
using IHC methods on either frozen or paraffin embedded tissues; however, only a few studies have evaluated IHC and RIA simultaneously from pathologic
specimens.15–16 Previous studies have shown reason-
2088
CANCER November 15, 1999 / Volume 86 / Number 10
able concordance between the two methods; however,
in cases in which a correlation did not exist, the authors have proposed several explanations. One hypothesis is that, in cases in which a tumor is RIA
positive but IHC negative, the fixation of the tissues
may alter the antigenic site of the protein receptor,
thus leading to the discordant result.4 In addition,
another hypothesis suggests that delay in tissue handling may lead to partial proteolysis of the tissues,
thus resulting in negative IHC results, whereas RIA
hormone receptor levels are found to be elevated.
In this study, there was excellent concordance
between the IHC results and the RIA results using
Spearmans correlation coefficient; however, there still
were cases in which there was a disparity between
hormone receptor expression as determined by IHC
and RIA. These differences in hormone receptor expression may be explained by the technical limitations
of the biochemical assay. Unlike breast carcinoma,
which is surrounded by stromal tissues that contain
no or relatively low levels of receptor, endometrial
carcinoma is involved intimately with benign stroma
that may contain significant amounts of receptor, thus
elevating the hormone receptor levels falsely when
measured by RIA.16 This may lead to erroneous results
when measuring hormone receptors in whole-tissue
homogenates. Several other studies also have suggested that IHC should be used for determination of
hormone receptor levels because of the inaccuracies
found with use of RIA.10,15,17,18 However, we acknowledge that any quantitation of immunohistochemical
stains is an inexact science and that a certain interobserver variability exists. Fortunately, this is an issue
only in the very small subset of patients who produce
borderline negative or positive results, and it may be
less significant than the often arbitrary choice of cutoff values used in biochemical assays.
In the current study, there were 12 patients who
were ER negative and PR positive as determined by
RIA but not by IHC analysis. Biologically, the expression of PR is dependent on ER for up-regulation;
therefore, there should not be any PR positive tumors
without the influence of estrogen. Initially, as seen in
Figure 1D, we concluded that PR levels determined by
RIA were elevated falsely, because the benign stroma
adjacent to the carcinoma strongly expressed PR. In
addition, there were 12 patients with a negative ER
status determined by RIA who, by IHC, were found to
express ER in epithelial cells. Therefore, in addition to
concluding that RIA does not allow one to control for
the stromal component, we propose that freeze-thaw
artifact prior to performing RIA may interfere with
ligand binding, leading to false negative ER status.
Because there were so few deaths in our study, we
chose to evaluate disease recurrence as the endpoint.
In this study, when evaluating the correlation between
hormone receptor status and tumor recurrence, ER
status determined by IHC was the most predictive of
recurrent disease. This is in contrast to other studies in
which it was found that PR status, and not ER status,
was the more significant prognostic factor.7–11 Because the majority of recurrences occurred among
Stage I patients, the regression models were applied to
these patients in a separate analysis. Even after controlling for tumor grade, ER status still was found to be
more significant than PR status as a prognostic factor.
Other studies have evaluated hormone receptor status
as a prognostic factor for death, and the results are
variable. In a study evaluating 175 patients, survival
was superior in patients with PR positive tumors,
whereas ER status did not correlate with survival.8
Similarly, other investigators, using biochemical and
immunohistochemical methods, have observed that
PR status, and not ER status, was correlated with death
from disease.9,10 However, only one study using RIA
and another study using IHC analysis found that ER
status was more predictive of patient survival.4,6
Whereas normal breast and endometrial epithelial
cells express ERs, loss of ER suggests a more advanced
molecular pathology with the deregulation of signaling pathways. Tumors that no longer express ER,
therefore, are removed further from the normal cellular phenotype and may be considered more aggressive
and refractory to therapy. Thus, the poor patient outcome associated with the absence of ER expression
may reflect a more malignant tumor course than
would be expected based only on the histologic diagnosis.
Clearly, there is significant disagreement in the
literature regarding the prognostic significance of ER
and PR status in patients with endometrial adenocarcinoma. To complicate the situation further, in clinical
practice, two very different methods have been used
to evaluate hormone receptor expression. This study,
in which both ER and PR were found to be related to
disease recurrence, reports that ER status, as determined by IHC, can be used as an independent predictor for disease recurrence. Clinically, this is useful
information, because IHC methodology is less expensive, more accurate, and easily performed on paraffin
embedded tissues. The numbers in this study were too
small to make a definitive statement on the importance of hormone receptor status in patients with
endometrial carcinoma; however, there should be
some consideration of using IHC to determine the
presence of ER as a prognostic factor in the clinical
management of these patients.
ER Predicts Endometrial Carcinoma Recurrence/Gehrig et al.
ACKNOWLEDGMENTS
The authors thank Elizabeth Allred for her assistance
with the statistical analysis.
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