ONCOLOGY
The prognostic value of molecular biomarkers
in tissue removed by curettage from FIGO stage
1 and 2 endometrioid type endometrial cancer
Anita Steinbakk, MD; Ivar Skaland, MSc; Einar Gudlaugsson, MD; Emiel A. M. Janssen, PhD; Kjell H. Kjellevold, MD;
Jan Klos, MD; Kjell Løvslett, MD; Bent Fiane, MD; Jan P. A. Baak, MD, PhD, FRCPath, FIAC(Hon)
OBJECTIVE:
To analyze the prognostic value of molecular biomarkers
in curettages of endometrioid endometrial cancer pathologic FIGO
stages 1 and 2.
STUDY DESIGN:
Population-based survival analysis in 258 patients of
classical prognostic features and molecular biomarkers of cell cycle
regulation, (anti)apoptosis, proliferation, squamous differentiation, and
PTEN/Akt pathway.
RESULTS:
With 74 months median follow-up (range, 1-209), 24
(9.3%) patients had metastases develop. Pathologic FIGO stage 2B
(6% of all cases) and age Ͼ 68 years had independent multivariate
prognostic value. Many molecular biomarkers were prognostic, partic-
ularly cell-cycle regulators p16, p21, p27, p53, p63, and the antiapop-
tosis marker survivin (which mostly stains mitoses). The strong prog-
nostic value of a multivariate model with survivin, p21, and p53
overshadowed all other prognosticators in pathologic FIGO 1 and 2A.
CONCLUSION:
In pathologic FIGO stage 1 and 2A endometrioid endo-
metrial cancer curettages, combined biomarkers survivin, p21, and
p53 expression patterns are prognostically stronger than classical fea-
ture combinations.
Key words: endometrial cancer, endometrioid, pathologic FIGO 1
and 2, prognosis
Cite this article as: Steinbakk A, Skaland I, Gudlaugsson E, et al. The prognostic value of molecular biomarkers in tissue removed by curettage from FIGO stage 1
and 2 endometrioid type endometrial cancer. Am J Obstet Gynecol 2009;200:78.e1-78.e8.
E
ndometrial carcinoma is the most
frequent gynecologic cancer. The
disease-related death rate in FIGO stage
2B-4 is high (20-80% and higher) and
even in the much more frequent “favor-
able” early-stage FIGO 1-2A, the death
rate is still 5-15%
1,2
and for decades has
been stable.
3
This motivates the develop-
ment of other prognosticators to enable
more accurate triaging of patients con-
cerning treatment modalities and to gain
better cell-biologic insight into the
disease.
In early FIGO stage 1-2A cancers, age,
histologic type, grade, and myometrium
invasion (MI) depth predict outcome.
2
Grade and MI are often used to deter-
mine individual therapy, but their prog-
nostic accuracy and reproducibility are
not always optimal.
3,4
Certain nuclear
morphometric features have proven to
be reproducible and strongly prognostic,
especially when combined with DNA
ploidy analysis.
3,5-8
DNA ploidy in itself
has strong prognostic value
3,9,10
but is
much less strong in curettages than in
hysterectomy specimens.
2
Moreover, ac-
curate high- and low-risk indicators
from curettage material are preferable
over that from hysterectomy in deter-
mining the extent of the hysterectomy
procedure.
In cancers of other organs, molecular
biomarkers are strong predictors of the
clinical progression of the disease. In en-
dometrial carcinoma, many molecular
factors, such as neovascularization/
vascular proliferation/vascular endothe-
lial growth factor,
11-15
p53,
16,17
anti-
apoptosis factors,
18,19
proliferation fac-
tors,
3,20-22
steroid receptors,
23,24
p16,
25
plasminogen activator inhibitor,
26
and
tumor-associated macrophages
15,27
are
promising. However, in many studies,
mixtures of early- and late-stage cancers
have been analyzed, which are molecular
biologically heterogeneous. Because ad-
vanced cancers have naturally accumu-
lated greater genetic damage than early
cancers, the results of these studies may
not be directly extrapolated to early can-
cers. Moreover, histologic types 1 and 2
cancers are often studied simulta-
neously, even though little information
is available as to the exclusive value of
these markers in the most frequent his-
tologic subtype, endometrioid endome-
trial cancers. The other histologic sub-
types follow different molecular
From the Departments of Pathology (Drs
Steinbakk, Gudlaugsson, Janssen,
Kjellevold, Klos, and Baak and Mr
Skaland) and Gynecology (Drs Steinbakk,
Løvslett, and Fiane), Stavanger University
Hospital, Stavanger, Norway; the Gade
Institute (Drs Steinbakk, Gudlaugsson,
and Baak and Mr Skaland), University of
Bergen, Bergen, Norway; and the Free
University (Dr Baak), Amsterdam, The
Netherlands.
Received Feb. 12, 2008; revised June 18,
2008; accepted July 8, 2008.
Reprints: Jan Baak, MD, Department of
Pathology, Stavanger University Hospital,
Armauer Hansensvei 20, 4068, Stavanger,
Norway. jpabaak@yahoo.com.
Dr Steinbakk is the recipient of Grant 911268
from Helse Vest, where she is a doctoral student.
0002-9378/$36.00
© 2009 Mosby, Inc. All rights reserved.
doi: 10.1016/j.ajog.2008.07.020
Research
www.
AJOG
.org
78.e1
American Journal of Obstetrics & Gynecology JANUARY 2009