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Molecular Oncology, Markers, Clinical Correlates |
Departments of Cancer Biology [S-K. K., R. S., L. G., G-H. H., L. H. F., L. B. C.] and Adult Oncology [P. R., A. E.], Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02115
An
automated rare event detection system (Rare Event Imaging System) is
described for the recognition of cancer cells that appear at low
frequencies (1 in 1 million) in peripheral blood (PB) or bone marrow
(BM). The instrumentation includes an automated fluorescence microscope
(Nikon Microphot-FXA) with a cooled charge coupled device camera
and a 60-MHz Pentium personal computer. Main features of the system are
rapid analysis of large microscopic fields, including a total cell
count, detection of fluorescently labeled cells, and a display of
digitally stored images of the detected cells. Furthermore, the
X,Y coordinates of each identified object
are stored and can be recalled for morphological analysis of the cell
using higher magnification or different fluorescent filter sets. The
preparation of the blood or BM samples for automated analysis consists
of lysis of the RBCs, attachment of sample cells onto adhesion slides,
fixation, and fluorescent labeling with anticytokeratin antibodies.
Cytokeratin-positive cells, however, were detected in 17% of the
samples from healthy blood donors using this procedure (mean number,
7/106 mononuclear cells in positive samples). To improve
the specificity of the rare event detection, a double-labeling protocol
combining intracellular cytokeratin with epithelial cell adhesion
molecule (Ep-CAM) (breast, ovarian, colon, and lung carcinoma
antigen) or disialo-ganglioside (GD2) antigen (small cell lung
carcinoma, neuroblastoma, melanoma antigen) was developed. Examples of
doubly labeled cultured cells and cancer cells from breast and small
cell lung cancer patients are shown. Using the double-labeling
protocol, no "positive" cells were seen in samples of healthy blood
donors. Automated rare event detection (cytokeratin single-staining)
was applied to 355 PB, BM, and stem cell (SC) samples from breast
cancer patients before autologous BM transplantation.
Cytokeratin-positive cells were found in 52% of BM, 35% of PB, and
27% of SC samples at frequencies of 1–1020 positive
cells/106 mononuclear cells, thereby establishing the
efficacy of the technique in the detection of rare cancer cells in
hematopoietic tissue samples of cancer patients.
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