A003
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DIAGNOSTIC, PROGNOSTIC AND THERAPEUTIC IMPACT OF QUANTITATIVE AND
MOLECULAR PATHOLOGY IN ENDOMETRIAL HYPERPLASIA AND CARCINOMA
Baak JPA 1, Mutter GL 2
1) Departments of Pathology, University Hospital VU, Amsterdam
and Medical Center Alkmaar, Netherlands,
2) Brigham and Women's Hospital, Harvard Medical School, Boston,
Massachussets, USA
Endometrial hyperplasia (EH) is a frequently occurring disease. In
the European Community (275 million inhabitants), an estimated number
of 75,000 new cases occurs per year. 10 to 20% progress to cancer.
Three major problems occur.
1) Diagnostic problem: to distinguish hyperplasias from cancer (considerable
intra- and interobserver variability occurs; 2) Prognostic problem:
prediction of progression-or-not to cancer is inaccurate, also with the
WHO classification and 3) Discrimination of risk-bearing hyperplasias from
benign conditions. As a result, considerable overtreatment occurs. This can
have serious psychological and sexual problems, and also result in
unnecessary costs for the national health care budget.
Over the past 20 years, we have developed a computerized morphometric
analysis (CMA) technique, that consists of a measurement tool, and an expert
system based classification tool. With the 4-class rule, endometrial
curettings or hysterectomy specimens are classified as morphometric low or
high grade hyperplasia, morphometric low or high grade carcinoma. For each
class, a numerical classification probability is calculated. Routine
application of CMA over the past two decades in different laboratories has
regularly corrected subjective classification by pathologists. In carcinomas,
the 4-class rule correlates better with depth of myometrial invasion than
subjective grade.
In subsequent studies, the D-score was developed to predict the outcome
of EH. DNA ploidy assessed by FCM was of no value, but morphometric analysis
is useful. With a multivariate D-score, specificity is equal to, or better
than with the usual WHO classification, but the sensitivity of the D-score
is better (1). This was confirmed in "the Philadelphia study" an independent
blind multicenter collaboration (2) on 45 cases (sensitivity 100%,
specificity 88.5%). Because of these findings, CMA generated D-score is
routinely applied in EH in a number of laboratories and therapy is guided
by the CMA classification. It is estimated that nationwide application in
the Netherlands will save approximately 15 million USD per year, due to
prevention of unnecessary hysterectomies.
Another promising approach to improve diagnostic accuracy is to the
study the monoclonal nature of endometrial precancers that can be used as
an informative biologic endpoint to evaluate the accuracy for morphologic
diagnosis. We have tested the ability of objective computerized morphometry
to diagnose monoclonal putative endometrial precancers. 93 nonmalignant
areas of endometrium from 64 uteri of women with coexisting endometrial
adenocarcinoma were scored as monoclonal (n=39) or polyclonal (n=54) by
PCR analysis (monoclonal by either non-random X chromosome inactivation
or clonal outgrowth of altered microsatellites). Polyps and progesterone
altered endometrium were excluded. Morphometry of corresponding delineated
regions on H&E stained sections was performed with the QProdit 6.1 image
analysis expert system. Lesions were evaluated by 4 independent experienced
gynaecopathologists. We also measured D-scores, incorporating standard
deviation of short nuclear axis, % stromal volume, and gland outer surface
density. The lesions then were classed as probable monoclonal (D<0, n=48),
unknown (01, n=42).The D-scores were
highly reproducible (inter-observer r>0.98), predicting monoclonal lesions
with 95% sensitivity and 75% specificity, and polyclonal areas with 95%
specificity and 77% sensitivity. Computerized image analysis is thus capable
of recognizing monoclonal endometrial precancers with specificity and
sensitivity at least comparable to (and usually higher than) that of
experienced pathologists, with the additional advantage of excellent
reproducibility.
In FIGO stage I endometrial cancer patients, histologic type and grade
are correlated with prognosis and used for therapeutic decision making.
However, assessment of these histologic features is subjective, and the
results are not always perfectly reproducible. Contrarily, previous studies
have shown that DNA-ploidy and morphometric features are highly reproducible
and have a strong prognostic value in these cancers. Multivariate analysis
has demonstrated that a combination of mean shortest nuclear axis (MSNA),
DNA-ploidy and depth of myometrial invasion (the so-called ECPI-1 score)
overshadowed the value of all other features investigated (3). An independent
retrospective long-term study (10-15 years follow-up) confirmed the
prognostic value of the ECPI-1 score in FIGO I Endometrial cancers
(only 2 (=3%) of 64 cases with low ECPI-1 values died, in contrast to 11 of
13 cases with high values (p <0.0001, Mantel-Cox value = 51.1)(4).
In early 1987, we therefore started a prospective multicenter evaluation in
the Netherlands, in which 26 hospitals participated. In total, 632 patients
have been enrolled. An interim analysis in June 1998 again showed the
overriding prognostic value of morphometric and cytometric analysis, also
in subgroup of FIGO I. FIGO I cases with high ECPI-values have a prognosis
similar to FIGO III cancers and therefore should be considered for adjuvant
chemotherapy.
It is concluded that quantitative pathology has essential diagnostic,
prognostic and therapeutic impact in the management of endometrial
hyperplasias and cancers. Supported by grants #28-1203 to
J.P.A.B. from the Dutch Praeventiefonds and # EDT-86 to G.L.M.
from the American Cancer Society
References:
1 Path. Res. Pract. 1992; 188:856-859
2 Am. J. Obstet. Gynecol. 1996; 174:1518-1521
3 Cancer 1989; 63:1378-1387
4 Int. J. Gynecol. Cancer 1995;5:112-116