Detection of Minimal Disease by Scanning Cytometry

K. Bauer
Chief Science Officer, Chromavision Medical Systems, Inc., San Juan Capistrano, California, USA

The presence of occult bone marrow metastases (OM) has been reported to represent an important prognostic indicator for patients with operable breast cancer and other malignancies. Assaying for the presence of OM most commonly involves labor-intensive manual microscopy including the requirement to detect one or more tumor cells in a background of 105-106 normal mononuclear cells. This presentation examines the use of automated cellular image analysis to identify occult breast carcinoma cells in bone marrow specimens using a recently developed instrument (ACIS, ChromaVision Medical Systems, Inc.)

Bone marrow analysis was performed following immunocytochemical staining. Specimens used in this study include normal bone marrow (n=10), bone marrow spiked with carcinoma cells (n=20), and bone marrow obtained from breast cancer patients (n=39). Reproducibility of the automated analysis for tumor cell detection was examined by having a pathologist evaluate montage images generated by the ACIS from a series of five bone marrow specimens from breast carcinoma patients. These were analyzed using three separate ACIS instruments in which analysis was separately performed on multiple (three to five) separate occasions for each instrument. Highly reproducible performance of the ACIS for tumor cell detection was demonstrated in these studies: Independent ACIS-assisted analysis of individual specimens resulted in the detection of an identical number of tumor cells in all instrument runs.

Further studies were performed to analyze OM from 39 breast cancer patients with two pathologists performing parallel analysis using either manual microscopy or ACIS-assisted analysis. In 17 of the 39 cases (44%), specimens were classified by the pathologist as positive for tumor cells following ACIS-assisted analysis, whereas the same pathologist failed to identify tumor cells on the same slides following analysis by manual microscopy. Reanalysis by pathologist blinded to their original results indicated that the disparity between manual microscopy and ACIS-assisted analysis reflected a significant rate of false negative determinations by conventional manual microscopy. Comparison of manual microscopy vs ACIS-assisted analysis in terms of the time required to review slides for interpreting a case for OM status revealed that automated cellular imaging reduced review time by approximately 12-fold.

Early efforts demonstrating the feasibility for analyzing peripheral blood specimens for the presence of rare (10-8) circulating carcinoma cells in peripheral blood will also be discussed. These studies indicate that the ACIS-assisted analysis provides excellent sensitivity, reproducibility, and sensitivity for the detection of OM and circulating carcinoma cells, relative to manual microscopy. Such performance may enable both improved assay standardization as well as an improved approach for guiding patient management and therapeutic targeting for drug discovery.

Presented at the XIVth International Symposium on Technological Innovations in Laboratory Hematology, held May 9-12, 2001 in Montpellier, France.

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