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2147
Immunohistochemically Detected p53 and HER-2/neu
Expression and Nuclear DNA Content in Familial
Epithelial Ovarian Carcinomas
Annika Auranen, M.D., Ph.D.1
Seija Grénman, M.D., Ph.D.1
Pekka-Juhani Klemi, M.D., Ph.D.2
BACKGROUND. Some epithelial ovarian carcinomas tend to occur more frequently
in certain families. This clustering may be due to a genetic predisposition, but the
role of inherited susceptibility in all families with multiple cases of ovarian carci-
1
Department of Obstetrics and Gynecology,
Turku University Hospital, Turku, Finland.
2
Department of Pathology, Turku University
Hospital, Turku, Finland.
noma is currently unresolved. Studies characterizing familial ovarian carcinomas
are few.
METHODS. From a population-based study of 559 patients with epithelial ovarian
carcinoma, 27 families with 2 or more ovarian carcinoma cases occurring in firstdegree relatives were identified. Histopathology, ploidy, and immunohistochemically detected p53 and HER-2/neu expression in these tumors were examined.
RESULTS. The mean age of the patients with familial ovarian carcinoma was 56.7
years. Approximately 67% of the tumors were either serous or undifferentiated
adenocarcinomas. The percentage of aneuploid tumors was 46%, that of p53 positive tumors was 51%, and that of HER-2/neu positive tumors was 69%. When the
families were divided into families with cases of breast carcinoma in addition to
ovarian carcinoma cases and/or ovarian carcinoma in 2 consecutive generations
(12 families) and families with ovarian carcinoma occurring in sisters only without
cases of breast carcinoma (15 families), no differences were noted in the frequency
of any of the studied variables.
CONCLUSIONS. Familial ovarian carcinomas do not appear to differ from sporadic
ovarian carcinomas with regard to patient age at presentation, histopathology,
ploidy, and immunohistochemically detected p53 expression. Immunohistochemically detected HER-2/neu expression was found to occur more frequently in familial ovarian carcinomas than has been reported in sporadic ovarian carcinomas.
Cancer 1997;79:2147–53. q 1997 American Cancer Society.
KEYWORDS: ovarian carcinoma, familial, flow cytometry, DNA ploidy, p53, HER-2/
neu, oncogenes, tumor suppressor genes.
Published previously as part of Annika Auranen’s Ph.D. thesis in the Turku University Publication Series, December 1996.
Supported by the Southwestern Division of the
Finnish Cancer Foundation, the Southwestern
Division of the Finnish Culture Foundation, and
the Research Fund of the Finnish Gynecological
Association.
Address for reprints: Annika Auranen, M.D., Department of Obstetrics and Gynecology, Turku
University Hospital, FIN-20520 Turku, Finland.
Received October 21, 1996; revision received
January 23, 1997; accepted February 27, 1997.
A
pproximately 2 – 5% of patients with epithelial ovarian carcinoma
have a first-degree relative affected with the same disease.1 – 4 Although this may partly be explained by chance only, epidemiologic
studies have convincingly demonstrated that the first-degree relatives
of ovarian carcinoma patients have an increased risk for the disease.1,2,4 – 7 Specific etiologic factors are thus likely to cause a proportion of this observed pattern.
Genes responsible for a dominantly inherited predisposition to
epithelial ovarian carcinoma recently have been identified. Mutations
in the BRCA1 and BRCA2 genes predispose to both breast and ovarian
carcinoma.8 – 11 Mutations in genes involved in the hereditary nonpolyposis colorectal carcinoma also predispose to ovarian carcinoma.12
However, the majority of patients with a family history of ovarian
q 1997 American Cancer Society
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CANCER June 1, 1997 / Volume 79 / Number 11
carcinoma have only one affected relative, and do not
fulfill the criteria for a dominantly inherited cancer
syndrome.1,2,4,13,14 The role of the dominantly inherited
genes predisposing to cancer in these families is currently unresolved.
Studies characterizing familial ovarian carcinomas
are few.3,13,15 – 17 Available studies have not been able
to detect any features, relating either to clinical picture
or tumor characteristics, that would clearly differentiate familial ovarian carcinomas from sporadic ones.
However, serous and undifferentiated adenocarcinomas appear to predominate. Early-onset ovarian carcinoma has been noted in families with several affected
relatives,18 but most studies have detected no difference in the median age of onset between familial and
sporadic ovarian carcinomas.3,13,16,19
From a population-based study of 559 Finnish epithelial ovarian carcinoma patients,4 the authors identified 27 families with ¢2 ovarian carcinoma cases
among first-degree relatives. To study the clinical and
biologic characteristics of familial ovarian carcinomas,
the authors obtained the paraffin embedded tumor
samples and the hospital records of these patients.
The authors examined the histology, DNA ploidy, and
immunohistochemically detected p53 and HER-2/neu
expression in these tumors to specify the role of these
features in familial ovarian carcinoma.
MATERIALS AND METHODS
Patients
The patients were identified from a population – based
study on cancer incidence in the first-degree relatives
of ovarian carcinoma patients. The details of the study
are described elsewhere.4 Briefly, women diagnosed
with epithelial ovarian carcinoma before the age of 76
years during the years 1980 – 1982 were searched for
in the Finnish Cancer Registry. Altogether there were
863 such women. The first-degree relatives (parents,
siblings, and children) of these women were identified
from the local parishes and from the National Population Registry. Complete family information with complete follow-up of all family members was obtained
for 559 families.
Cancer occurrence in the family members from
these 559 families was checked using the Finnish Cancer Registry. Because the Finnish Cancer Registry was
founded in 1952, cancer occurrence in relatives who
died before the foundation of the Registry was checked
using death certificates. Death certificates were not
available for relatives who died before 1936.
Altogether, 27 of the 559 women with ovarian carcinoma had a first-degree relative with ovarian carcinoma. In 23 families, 2 ovarian carcinoma cases were
identified and in 4 families 3 ovarian carcinoma cases
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were identified. In these 27 families, 58 ovarian carcinomas and 27 cancers of other primary sites were detected.
The hospital records and paraffin embedded tumor tissue blocks of the 58 ovarian carcinoma patients
were requested from the relevant hospitals and pathology laboratories. Tumor samples were obtained
for 39 ovarian carcinoma patients; complete hospital
records were obtained for 27 of these women. Of the
27 ovarian carcinoma families, no samples were obtained for 4 families. For nine families, samples for
only one family member were obtained. For 12 families, samples for 2 patients were obtained and for 2
families samples for 3 patients were obtained.
Based on the phenotypic appearance of the family,
the families were subdivided into 2 groups: 1) families
with a minimum of 2 ovarian carcinoma cases and 1
breast carcinoma case and/or families with ovarian
carcinoma in 2 successive generations (12 families),
and 2) families with ovarian carcinoma occurring in
sisters only and no breast carcinoma cases in the family (15 families). This subdivision was based on an
article reporting that 92% of families with 3 breast
carcinoma cases and/or ovarian carcinoma cases were
linked to the BRCA1 locus.11 Because site specific ovarian carcinoma also has been reported in some families
to be linked to the BRCA1 locus,20 families showing
dominant transmission of ovarian carcinoma were
grouped together with the breast-ovarian carcinoma
families.
Clinical Characteristics
All 58 patients were included in the calculation of the
mean ages at diagnosis. With regard to the evaluation
of tumor characteristics, only the 39 patients with
available tumor samples were included. Clinical staging was redone by a gynecologic oncologist for all 39
patients with tissue blocks and pathologic reports according to the International Federation of Gynecology
and Obstetrics staging system.21
Histopathology
The original histology slides were reviewed and new
van Gieson and hematoxylin and eosin stained 4-mm
sections were used for reclassification of the tumors
(performed by P.K.) according to the World Health
Organization classification.22 The tumors were graded
into well, moderately, poorly differentiated, and undifferentiated carcinomas.23
Flow Cytometry
The preparation of a single cell suspension from paraffin
embedded tissue was performed as previously described.24,25 The samples were analyzed with a FACScan
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2149
flow cytometer (Becton-Dickinson Immunocytometry
Systems, Braintree, MA). The peak with the least DNA
content was considered to represent diploid cells. If only
one G1 peak could be observed in the DNA histogram,
the tumor was considered to be diploid. Tumors with
two G1 peaks were considered to be aneuploid.
Immunohistochemistry
Immunohistochemical staining with two p53 antibodies and one HER-2/neu antibody was performed with
the avidin-biotin method as described previously.26
New 4-mm sections cut from the original paraffin
blocks on slides were processed as described earlier
and incubated overnight at 4 7C in 1% bovine serum
albumin (BSA) with the primary mouse antibody for
p53 diluted in 1:800 (DO-7; DAKO, Copenhagen, Denmark), the primary mouse antibody for p53 diluted
in 1:200 (NCL-p53-DO7; Novocastra, Newcastle-uponTyne, United Kingdom), or the primary rabbit antibody for HER-2/neu diluted in 1:200 (A 485; DAKO).
Counterstaining was performed with Mayer hematoxylin, after which the slides were dehydrated in
alcohol series and xylene and mounted. Sections
treated with 1% BSA without the primary antibody
(p53) and sections treated with normal serum at a
dilution of 1:5000 (HER-2/neu) served as negative controls. Because p53 staining was performed for all samples with two different antibodies and concordant
staining was required, no positive p53 control was
used. A section of ovarian carcinoma previously determined to be positive for HER-2/neu was used as a
positive control for HER-2/neu.
The staining result was assessed with a light microscope. The percentage of tumor cells on the slide was
first evaluated, after which the percentage of positive tumor cells was estimated. For p53, the staining was considered to be positive if nuclear staining was observed. The
intensity of the staining was classified between 0: no staining and 3: most intense staining. For HER-2/neu, cell
membrane staining was required for a positive result. The
intensity of the staining was classified similarly between
0: no staining and 3: most intense staining.
The tumors were classified as p53 positive if intensity
of the nuclear staining of 2 or 3 was observed in ú20%
of the tumor cells (Fig. 1). To be classified as HER-2/neu
positive, an intensity of ¢1 in the cell membranes of
ú20% of the tumor cells was required (Fig. 2).
Statistical Analysis
The mean age at diagnosis of the 58 patients with
familial ovarian carcinomas was compared with the
mean age at diagnosis of the 532 ovarian carcinoma
patients with no family history of ovarian carcinoma.
The differences between mean ages at diagnosis and
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FIGURE 1. A photomicrograph of p53 positive ovarian carcinoma (original magnification 1250).
FIGURE 2.
A photomicrograph of HER-2/neu positive cells in a clear
cell carcinoma of the ovary. The cell membrane is stained positive (original
magnification 1250).
tumor characteristics in the two familial ovarian carcinoma subgroups were analyzed using the chi-square
test or Fisher’s exact test. The difference was considered to be statistically significant if the P value was õ
0.05. All P values were two-tailed.
In 14 families, tumor samples from ¢2 ovarian
carcinoma patients could be analyzed. The number of
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TABLE 1
Mean Age at Diagnosis, Histology, Grade, Ploidy, and Immunohistochemically Detected Expression of p53 and
HER-2/neu in Patients with Familial Ovarian Carcinomas
Factor
All families
Breast-ovarian carcinoma/
two-generation ovarian
carcinoma families
Mean age at dg (yrs)
No. of tumors
Histology (%)
Serous
Mucinous
Endometrioid
Clear cell
Sertoli’s cell
Transitional
Undifferentiated
Grade (%)
1
2
3
Ploidy (%)
Diploid
Aneuploid
p53 expression (%)
Positive
Negative
HER-2/neu expression (%)
Positive
Negative
56.7
39
56.8
14
55.8
25
14 (36)
2 (5)
5 (13)
3 (8)
1 (3)
2 (5)
12 (31)
6 (43)
1 (7)
3 (21)
—
—
—
4 (29)
8 (32)
1 (4)
2 (8)
3 (12)
1 (4)
2 (8)
8 (32)
6 (15)
8 (21)
25 (64)
3 (21)
3 (21)
8 (57)
3 (12)
5 (20)
17 (68)
21 (54)
18 (46)
10 (71)
4 (29)
11 (44)
14 (56)
20 (51)
19 (49)
7 (50)
7 (50)
13 (52)
12 (48)
27 (69)
12 (31)
8 (57)
6 (43)
19 (76)
6 (24)
One-generation ovarian
carcinoma families
dg: diagnosis.
TABLE 2
Intrafamilial Concordance for Histology, Grade, Ploidy, p53, and HER-2/neu Expression in the 14 Families
with Two or More Ovarian Carcinoma Samples
No. of families
Breast-ovarian carcinoma/two-generation
ovarian carcinoma families
20
25
27
35
One-generation ovarian carcinoma families
10
18
19
22
23
28
29
32
33
36
Total/variable
Histology
Grade
Ploidy
p53
HER-2/neu
Concordance
index
0
/(S)
0
0
0
/(3)
0
/(3)
0
/(D)
/(D)
/(D)
/(neg)
0
/(neg)
0
/(pos)
/(pos)
0
0
0.4
0.8
0.4
0.4
0
0
0
/(U)
/(S)
0
/(U)
0
0
0
4/14
0
/(1)
0
/(3)
0
0
0
/(2)
/(3)
/(3)
7/14
0
0
/(A)
0
/(D)
/(D)
0
0
/(A)
/(A)
8/14
/(pos)
/(neg)
0
0
0
0
0
/(neg)
0
0
5/14
/(pos)
0
/(pos)
0
0
/(neg)
0
/(pos)
/(pos)
/(pos)
8/14
0.4
0.4
0.4
0.4
0.4
0.4
0.2
0.6
0.6
0.6
0.4
/: tumors concordant for the examined variable; 0: tumors discordant for the examined variable; S: serous; D: diploid; A: aneuploid; neg: negative immunostaining;
pos: positive immunostaining; U: undifferentiated.
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carcinoma and the 532 women without a family history of ovarian carcinoma (56.7 years vs. 55.8 years),
nor was there a significant difference between the
mean age at diagnosis of ovarian carcinoma in the two
subgroups of families (56.8 years vs. 55.8 years).
The majority of the tumors were either serous or
undifferentiated adenocarcinomas. There was no statistically significant difference between the two subgroups when histology, grade, ploidy, p53 expression,
and HER-2/neu expression were compared (Table 1).
The intrafamilial concordance of the studied parameters in the 14 families are presented in Table 2.
None of the examined five variables showed intrafamilial concordance in ú67% of the families. The mean
concordance index for all 14 families was 0.4.
In four families, three ovarian carcinoma cases
were diagnosed (Fig. 3). Of the 12 ovarian carcinomas
in these 4 families, tumor samples were obtained for
10. Seven of the ten tumors expressed HER-2/neu, with
intrafamilial concordance in expression in three families. Only four tumors expressed p53. Intrafamilial
concordance was observed in only one family, in
which all tumors were negative for p53 expression.
Three of the four families showed intrafamilial concordance with regard to ploidy.
DISCUSSION
FIGURE 3. Pedigrees of the four families with three ovarian carcinoma
patients with results of the tumor analysis. Circles: females; squares:
males; blackened circles: females with epithelial ovarian carcinoma; grey
circles or squares: persons with cancer at site other than ovary or breast;
gr: grade.
families concordant to either histology, grade, ploidy,
p53 expression, or HER-2/neu expression was calculated. To define intrafamiliar similarity of tumors, an
artificial concordance index with a maximum value of
1.0 was created. This index was comprised of the
above-mentioned five variables, each contributing to
the concordance index with a value of 0.2.
RESULTS
There was no significant difference between the mean
ages at diagnosis of the 58 women with familial ovarian
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Malignant transformation of epithelial ovarian cells
involves many genes, of which the tumor suppressor
gene p53 and protooncogene HER-2/neu are the most
intensely studied.27 Mutations in the p53 gene have
been reported to occur in 30 – 50% of ovarian carcinomas,26,28 – 30 but no consensus exists on the role of p53
mutations in disease progression and patient survival.26,29,31,32 Mutations in the HER-2/neu gene have
been reported to occur in 20 – 30% of ovarian carcinomas.33 – 36 Overexpression of HER-2/neu is suggested to
be associated with poor survival,33,34 but opposing
views have also been expressed.35,36 Approximately 60 –
90% of advanced stage ovarian carcinomas have been
reported to be aneuploid.37 – 39
In this set of familial ovarian carcinomas, the percentage of p53 positive tumors is within the range
reported in the literature, but the percentage of tumors
positive for HER-2/neu expression, nearly 70%, clearly
exceeds what is reported for sporadic tumors. If overexpression of HER-2/neu as detected by immunohistochemistry is an indication of amplification of the
HER-2/neu gene, this protooncogene is expressed differently in familial and sporadic ovarian carcinomas.
Previously, Buller et al. examined HER-2/neu expression with immunohistochemistry in familial ovarian
tumors15,17 and detected no HER-2/neu expression.
Although overexpression of HER-2/neu protein is
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usually the result of gene amplification, overexpression
has also been reported to occur without detectable gene
amplification.40 Immunohistochemistry has been reported to be sensitive to errors due to the method itself.41,42 Therefore, direct demonstration of HER-2/neu
gene amplification is required before it can be concluded
whether amplification of HER-2/neu is involved in the
pathogenesis of familial ovarian carcinoma.
The intrafamiliar similarity of familial ovarian carcinomas is of special interest because if a common
predisposing factor exists as a cause of ovarian carcinoma in these families, one would expect these carcinomas to show intrafamilial similarity in clinical or
biologic characteristics. It is therefore surprising that
in the 14 families with samples from ¢2 patients, so
few showed similarities in histology. Tumors with
germline mutations in the BRCA1 genes have been
serous or undifferentiated43 but of the four ovarian
tumors with germline BRCA2 mutations in a study by
Takahashi et al., two were serous, one was mixed serous and clear cell, and one was endometrioid,44 indicating that even in ovarian tumors histologic differentiation might vary due to mutations in a certain gene.
Because ploidy, p53 expression, and HER-2/neu
expression are factors that might be dependent on
progression of the disease,32,45 – 47 intrafamiliar differences in these variables are not unexpected. However,
when studying the concordance indexes of these 14
families, it must be concluded that either the examined variables are not fundamentally significant in the
development of familial ovarian carcinomas or that in
most of these families, a genetic predisposition does
not exist. Based on the authors’ previous study,4 they
were able to estimate the number of expected ovarian
carcinoma cases in these first-degree relatives. The expected number of ovarian carcinomas was 8.2, which
means that of these 27 families, multiple occurrence
of ovarian carcinoma would occur due to chance in
approximately 8.
A division of these families into two subgroups
based on phenotypic appearance revealed no significant differences. The division was performed in an
attempt to separate families possibly harboring inherited BRCA1 and BRCA2 gene mutations from families
less likely to have these mutations. Because this division is not based on molecular evidence, it is expected
that heterogeneity also exists inside these groups. The
authors classified all families with breast carcinoma
together, but the age range of the breast carcinoma
patients in these families was between 45 years to 81
years, and in 6 families breast carcinoma was diagnosed in patients older than 60 years. Because breast
carcinoma is a common disease, some of these cancers
are likely to be sporadic. However, a division according
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to more strict criteria, including only families with
breast carcinoma diagnosed before the age of 60 years,
did not change the results (data not shown).
In conclusion, the authors found that age at diagnosis, histology, ploidy, and immunohistochemically
detected p53 expression are not different in familial
ovarian carcinomas when compared with what is reported in sporadic ovarian carcinomas. Tumors from
families phenotypically appearing as having possible
BRCA1 or BRCA2 involvement were not different from
tumors from families without features suggesting
involvement of the BRCA1 gene. Immunohistochemically detected HER-2/neu expression in familial ovarian carcinoma was beyond that reported for sporadic
ovarian carcinoma, but amplification of the HER-2/
neu gene must be studied before conclusions regarding the role of this protooncogene in familial ovarian
carcinoma are made.
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