Dissertation committee:
Λάζαρης Ανδρέας, Καθηγητής, Ιατρική Σχολή, ΕΚΠΑ
Νόνη Αφροδίτη, Αναπληρώτρια Καθηγητρια , Ιατρική Σχολή, ΕΚΠΑ
Καβαντζάς Νικολαος, Καθηγητής, Ιατρική Σχολή, ΕΚΠΑ
Κουτσιλιέρης Μιχαήλ, Καθηγητής, Ιατρική Σχολή, ΕΚΠΑ
Φιλίππου Αναστάσιος, Καθηγητής, Ιατρική Σχολή, ΕΚΠΑ
Θυμαρά Ειρήνη, Επίκουρη Καθηγητρια, Ιατρική Σχολή, ΕΚΠΑ
Σακελλαρίου Στρατηγούλα, Επίκουρη Καθηγητρια, Ιατρική Σχολή, ΕΚΠΑ
Summary:
Objective: Endometrial carcinoma is one of the most common malignancies of the
female genital tract. Alterations in the expression levels of various oncogenes and tumor
suppressor genes serve important roles in the carcinogenesis and biological behavior of
endometrial carcinoma. Chronic hyperinsulinemia due to insulin resistance and
elevated levels of insulin-like growth factor (IGF)-1 and IGF-2 are suggestive of a
significantly higher risk of endometrial carcinoma. There is a wealth of evidence
showing differential expression of IGF-1 isoforms in various types of cancer.
Material and Methods: The aim of the present study was to evaluate retrospectively
in 99 archived endometrial carcinoma tissue sections the immunohistochemical protein
expression of p53, phosphatase and tensin homologue deleted on chromosome 10
(PTEN), survivin and IGF-1Ec isoform. In addition, the correlation of the expression
of these proteins with clinicopathological parameters was assessed. Furthermore, the
association was assessed between clinicopathological parameters and i) the
concomitant expression of p53 and PTEN expression, ii) the concomitant expression of
survivin and PTEN and p53 expression, and iii) the concomitant expression of IGF-1Ec
isoform and PTEN, p53 or survivin. Expression of IGF-1Ec was also assessed in nine
cases of non-neoplastic endometrial tissue adjacent to the tumor, in 30 cases with
normal endometrium and in 30 cases with endometrial hyperplasia.
Results: The overall rate of p53 and PTEN positivity was 89 and 77%, respectively,
according to the sum of stain intensity and scores of immunopositive cells.
Immunopositivity for survivin was identified in 88% of cases. IGF-1Ec expression was
high in non-endometrioid carcinoma (serous papillary or clear cell carcinoma)
compared with that in endometrioid adenocarcinoma. IGF-1Ec expression was also
high in the presence of tumoral necrosis. Notably, the sum of the immunohistochemical
expression of p53 was significantly correlated with patient age (P=0.037), histologic
type (P=0.008), histologic grade (P=0.002) and fallopian and/or ovarian invasion
(P=0.014). Furthermore, PTEN expression was associated with myometrial invasion
(ρ=-0.377; P=0.002) and clinical stage (P=0.019). A significant association was
identified between the sum of staining intensity and scores of survivin immunopositive
cells, and patient age (P=0.028), histological grade (P<0.001), clinical stage (P=0.018)
and fallopian tube and/or ovarian invasion (P=0.039). Furthermore, there was a
significant correlation between the histological differentiation and the sum of staining
intensity and the number of IGF-1Ec immunopositive cells in endometrial carcinoma.
The concomitant sum of p53 and PTEN expression was identified in 45% of patients
with endometrial adenocarcinoma. Concomitant survivin, PTEN and p53 expression
(staining scores and intensity) was observed in 60% of endometrial adenocarcinomas.
The sum of p53 positivity correlated strongly with PTEN expression (ρ=0.256;
P=0.044). In addition, concomitant p53 and PTEN expression was correlated with
patient age (P=0.008) and histologic differentiation (P=0.028). A negative tendency for
correlation was observed between surivin and PTEN immunostaining scores (P=0.062;
ρ=-0.238). Specimens with high scores of survivin expression tended to show decreased
scores of PTEN immunostaining, and vice versa. However, in circumstances with an
increased co-expression of survivin and PTEN, a statistically significant association
with histological types was observed (P=0.020). A statistically significant positive
correlation was identified between survivin and p53 sum co-expression (P=0.008;
ρ=0.300). Furthermore, a significant association was identified between survivin and
p53 concomitant sum expression and age of patients (P=0.001), histological type
(P=0.020), clinical stage (P=0.037), histological differentiation (P=0.001) and presence
of fallopian tube and/or ovarian invasion (P=0.026). In addition, there was a moderate
negative correlation between co-expression of IGF-1Ec and PTEN, for both the number
of immunopositive cells (P=0.006, ρ=-0.343) and the sum of staining (scores and
intensity; P=0.006, ρ=-0.343). Furthermore, there was a positive correlation between
the sum of staining (scores and intensity) and co-expression of IGF-1Ec and survivin
(P=0.043, ρ=0.225). However, there was no association between concomitant
expression of IGF-1Ec and p53.
Conclusions: The findings indicated a correlation between the expression of p53 and
PTEN in endometrial adenocarcinoma, which suggested an intrinsic association
between expression levels of these tumor suppressor genes. The study also suggested
that concomitant p53 and PTEN expression contributed in characterizing the tumor
behavior of endometrial carcinoma. Taken together, the present study suggested the
combined expression of p53 and PTEN in the development of high-grade endometrial
carcinoma in older patients. In addition, the findings indicated activation of different
molecular pathways in the tumor progression between low-grade and high-grade
endometrial carcinomas. Also, the findings suggested that survivin may be an indicator
of unfavorable outcome in older patients with endometrial carcinoma, in specific
circumstances that are dependent on different concomitant genetic alterations and
different combinations of molecular signaling pathways. Increased expression levels of
survivin and PTEN may serve a role in the development of more aggressive endometrial
carcinoma during their interaction. In addition, protein expression levels of survivin
and p53 are positively correlated and may share a common molecular pathway to
promote endometrial carcinogenesis. These findings provided evidence that survivin
and p53 combined may be useful markers for the prediction of tumor behavior and
prognosis. Finally, these results emphasized the importance of IGF-1Ec expression
during development of non-estrogen dependent endometrial adenocarcinoma. IGF-1Ec
and PTEN may function opposingly during endometrial carcinogenesis. By contrast,
IGF-1Ec and survivin may share common molecular pathways and may promote, in
parallel, tumoral development.
