Correlation of proliferation indices, apoptosis, and related oncogene expression (bcl-2 and c-erbB-2) and p53 in proliferative, hyperplastic, and malignant endometrium.
BACKGROUND
The various morphological groupings of endometrial pathology are often difficult to distinguish from each other. The endometrium is an actively proliferating tissue and there is an overlap in cell proliferation fraction (CPF) between benign proliferative endometrium (BPE) and endometrial carcinoma (EC). Apoptosis in benign cycling endometrium is related to the menstrual cycle. In this study we evaluated CPF, apoptosis, and oncogenes that relate to cell turnover (bcl-2, p53, and c-erbB-2) in the spectrum of endometrial pathology.


METHODS
We examined a total of 64 cases consisting of 10 cases of BPE, 18 cases of simple endometrial hyperplasia (SEH), 18 cases of complex hyperplasia (CEH; including eight cases with atypical hyperplasia), and 18 cases of EC, FIGO grade 1. CPF was measured by the mitotic index (MI) and by the percentage of Ki-67 positive nuclei (Ki-67 index). Apoptotic index (AI) was determined on hematoxylin and eosin sections.


RESULTS
MI was 2.48% in BPE, 0.65% in SEH, 0.6% in CEH, and 0.91% in EC (P < .00001). Ki-67 index was 38.44%, 16.4%, 23.25%, and 31.7% respectively (P < .00001). AI was 1.17%, 2.2%, 2.57%, and 3.31% respectively (P = .02). The AI/MI and AI/Ki-67 ratios were lowest in BPE and highest in SEH (P = .007). All cases of BPE, 84% of SEH cases, 77% of CEH cases, and 88% of EC cases displayed cytoplasmic and/or nuclear bcl-2 expression. Cytoplasmic bcl-2 expression increased from BPE to SEH, whereas it decreased in CEH and EC with emergence of only nuclear expression. Of the EC cases, 38.8% showed intense nuclear bcl-2 reactivity and a significantly higher Ki-67 index than cases with cytoplasmic expression (P = .01). No p53 or c-erbB-2 expression was seen in either BPE or EH. Of the EC cases, 50% were positive for p53 whereas 30% were positive for c-erbB-2. C-erbB-2-positive cases had a significantly higher Ki-67 index and AI than negative cases (P = .02). Cases of EC with p53 expression also had significantly higher AI (P = .01).


CONCLUSIONS
In actively proliferating tissues like endometrium, CPF does not correlate with progression to malignancy. In contrast, AI and derived AI/CPF ratios are better indicators of progression. The expression of p53, c-erbB-2, and nuclear bcl-2 in EC correlate with higher cell turnover indices (CPF and AI).
Department of Pathology, University of Maryland School of Medicine, Baltimore, USA.
O B
OB
Ioffe
J C
JC
Papadimitriou
C B
CB
Drachenberg
D000230:Adenocarcinoma / Q000235:genetics / Q000473:pathology; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017209:Apoptosis; D002455:Cell Division; D004714:Endometrial Hyperplasia / Q000235:genetics* / Q000473:pathology; D016889:Endometrial Neoplasms / Q000737:chemistry / Q000235:genetics* / Q000473:pathology; D004717:Endometrium / Q000166:cytology* / Q000473:pathology; D005260:Female; D015870:Gene Expression; D019254:Genes, bcl-2 / Q000235:genetics*; D018734:Genes, erbB-2 / Q000235:genetics*; D016158:Genes, p53 / Q000235:genetics*; D006801:Humans; D007124:Immunoenzyme Techniques; D019394:Ki-67 Antigen / Q000032:analysis; D008875:Middle Aged; D008938:Mitosis; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000032:analysis; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000032:analysis; D016159:Tumor Suppressor Protein p53 / Q000032:analysis
D019394:Ki-67 Antigen; D019253:Proto-Oncogene Proteins c-bcl-2; D018719:Erb-b2 Receptor Tyrosine Kinases; D016159:Tumor Suppressor Protein p53