Q & A

January 2003

Richard A. Savage, MD

Q. We do MIB-1 staining on sections of invasive breast cancers to estimate the size of the proliferative fraction. Excluding the use of image analysis to help quantify the percentage of tumor cell nuclei staining, do any reliable methodological guidelines exist beyond providing a rough estimate, such as small, large, or intermediate-sized proliferative fraction?

A. I recommend doing careful mitotic figure counts and recording the findings along with a carefully performed Bloom-Richardson grading of the invasive breast component. I don't recommend Ki-67 labeling. Previous studies have shown a close association between mitotic figure counts and Ki-67 and bromodeoxyuridine-labeling indices in breast carcinomas.^1,2

Moreover, I do not know of a good standardized technique or method for measuring and reporting Ki-67 labeling of breast carcinomas. Indeed, a recently published large multicenter study (172 participating laboratories) focused on the reproducibility of measuring Ki-67 labeling indices and found that excessive interlaboratory differences were the consequence of poor technique standardization.³

If we are to achieve useful reference values and standardization, I believe high, low, and intermediate controls should be run with each new breast case, much like laboratorians control such chemistry tests as calcium and lactate dehydrogenase. The results of the controls should fall within defined guidelines.

Because standardization of immunohistochemistry is not well developed, I recommend the less expensive and equivalent proliferation index of careful mitotic figure counting. I believe it works as well, has as much scientific merit, and provides as much useful information.

References

1. Weidner N, Moore DH II, Ljung BM, et al. Correlation of bromodeoxyuridine (BRDU) labeling of breast carcinoma cells with mitotic figure content and tumor grade. Am J Surg Pathol. 1993; 17: 987–994.
2. Weidner N, Moore DH II, Vartanian R. Correlation of Ki-67 antigen expression with mitotic figure index and tumor grade in breast carcinomas using the novel “paraffin”-reactive MIB1 antibody. Hum Pathol. 1994;25(4):337–342.
3. Mengel M, Von Wasielewski R, Wiese B, et al. Inter-laboratory and inter-observer reproducibility of immunohistochemical assessment of the Ki-67 labelling index in a large multi-centre trial. JPathol. 2002; 198(3): 292–299.

Q. What tests should we use to diagnose recurrent spontaneous abortion? Are any treatments available to resolve this condition?

A. Pregnancy loss typically occurs during the second trimester in patients who have antiphospholipid syndrome, or APS. The fetal loss rate in primary APS varies from 50 to 75 percent. Fetal loss rates are as high as 90 percent in patients who have systemic lupus erythematosus and secondary APS. There is a correlation between fetal loss rates and the antibody titer, most commonly IgG anticardiolipin. IgM anticardiolipin antibodies, however, also may play a role in recurrent spontaneous abortion.

Lupus anticoagulants should be ordered for evaluating patients with recurrent spontaneous abortion. The Staclot LA and dilute Russell viper venom time, or dRVVT, are the tests used by most laboratories to identify lupus anticoagulants. IgG and IgM anticardiolipin antibodies are also indicated.

Antibodies to β₂ glycoprotein I are thought to be significant in the pathogenesis of recurrent spontaneous abortion. Consequently, many laboratories now incorporate an enzyme-linked immunosorbent assay to detect antibodies to β₂ GPI. Antibodies to annexin V have also been suggested as an antigenic target associated with recurrent spontaneous abortion.

Bibliography

• Keswani SC, Chauhan N. Antiphospholipid syndrome. J R Soc Med. 2002; 95:336–342.
• Lockshin MD, Druzin ML. Antibody to cardiolipin as a predictor of fetal distress or death in pregnant patients with systemic lupus erythematosus. N Engl J Med. 1985; 313: 152–156.
• Mavragani CP, Vlachoyiannopoulos PG, et al. Antiphospholipid syndrome: current diagnostic and therapeutic issues. J Musculoskeletal Med. 2002; 186–193.

Q. What official accreditation or certification of quality is offered for laboratory information systems and laboratory information management systems?

A. Unfortunately, there is no official organization overseeing accreditation, certification, or quality assurance for most clinical laboratory information systems. The notable exception is in blood banking, where the Food and Drug Administration certifies software that handles blood donor or transfusion information.

The CAP Laboratory Accreditation Program’s laboratory general checklist includes many items that an LIS must provide to meet fundamental laboratory needs. There is, however, no published list of systems meeting these criteria. CAP TODAY publishes annually a tabulation of vendors marketing laboratory information systems, but it does not assess the quality of these products (CAP TODAY, November 2002, page 56).

For laboratory information management systems, or LIMS, which are used in analytic and some research laboratories, certification may be obtained through organizations affiliated with ASTM International (www.astm.org) or the American Society for Quality (www.asq.org). You should contact these organizations for additional information.

Finally, some vendors of medical information systems have chosen to become ISO-9001 certified, attesting to the general quality of their software development processes.

Raymond D. Aller, MD
CAP TODAY Contributing Editor
Clinical Information
Systems Consultant
Vista, Calif.