College of American Pathologists
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  Q & A





cap today

June 2001

Q.  I have a question about correlation between Pap tests—both regular and ThinPrep—and biopsy. What percentage is the benchmark? Some physicians are not satisfied with our service, and they seem to expect 100 percent correlation.

A.  The percentage of cytology-biopsy discrepancies depends on the definition of discrepancy and the methods used to track discrepancies. One discrepancy definition offered in the CAP Quality Improvement Manual in Anatomic Pathology is a difference in interpretation that would have an impact on patient management decisions.1 Another definition is a two-step interpretive difference, for example low-grade squamous intraepithelial lesion on biopsy versus squamous cancer on the Pap. Excluding certain specimen types, for example endocervical curettings, will also have an impact on the discrepancy rates. Finally, the time interval and number of specimens considered per patient (single versus multiple cytology-histology combinations) will also affect the calculation.

A discordant Pap-biopsy combination, as defined by Joste et al, is one “in which one of the specimens is reported as a significant squamous or glandular lesion and the other specimen is reported as within normal limits.”2 This definition excluded atypical squamous cells of undetermined significance and biopsies lacking the transformation zone. In their 14-month study of 56,497 cervical smears, 2.8 percent (1,582) were followed by cervical biopsy. Of 1,582 paired samples, 175 cases (11 percent) were identified as discrepant. (This group represents 0.3 percent of all smears reviewed.) In a vast majority (93.2 percent) both cytologic and histologic diagnoses were confirmed and the discrepancies were classified as sampling errors. Only 3.4 percent of cases were found to have correctable (interpretive or screening) errors. Tritz et al also found an 11 percent discrepancy rate, with the majority representing sampling issues, although the definition of discrepancy involved a two-step difference in interpretation.3

Jones and Novis reported results of 12 months' followup of 16,132 cervical smears from 306 laboratories as part of a CAP Q-Probes evaluation.4 They found that 18 percent of patients with low-grade squamous intraepithelial lesion on cytology had high-grade squamous intraepithelial lesion, or HSIL, on followup biopsy. Only 67 percent of patients with LSIL on cytology had LSIL on biopsy, and 86.5 percent had any abnormal biopsy. Of those patients with HSIL on smear, 15.5 percent had LSIL on corresponding biopsy, 75.5 percent had HSIL on biopsy, and 93.5 percent had an abnormal biopsy.4 Similar to the American experience, the United Kingdom’s screening program ranges between 65 and 85 percent concordance for biopsy-proven HSIL after HSIL on cervical smear.5

Brown et al evaluated 48 discrepant cases of HSIL on cervical smears with corresponding biopsies revealing LSIL.6 Biopsy specimens were tested and typed for HPV with molecular techniques. Thirty-seven cases were positive for HPV DNA: two for low-risk HPV types, 17 for high-risk types, and 18 for types of unknown oncogenicity. The prevalence of high-risk HPV was significantly higher in LSIL biopsies with a history of HSIL smears.6

Some cytology-histology discrepancy data have also been reported using liquid-based cytology. For example, Diaz-Rosario and Kabawat reported that 20.9 percent of HSIL ThinPreps and 26.8 percent of LSIL ThinPreps were followed by negative biopsies.7

It is unrealistic to expect 100 percent correlation between cervical cytology and cervical biopsies, and an open discussion with concerned clinicians is recommended. Cervical cytology is appropriately used as a screening test, which means that some specificity will be sacrificed for increased sensitivity, while the colposcopically guided cervical biopsy is recommended as a confirmatory test. Both tests are subject to sampling error. Although the cervical biopsy is often considered the gold standard, not all lesions will be fully characterized on an initial colposcopy, and a lesion that is small or deep in the glands may not be sampled. Some lesions will regress in the interval between the Pap test and the colposcopy. In some cases, the cervical smear may better represent the pathology of the cervix than the biopsy.2-6 Appropriate treatment and followup should then be dictated by a combination of clinical, cytology, and biopsy data. In addition, the pathologist's advice or report comments may be extremely helpful.

1. Travers H, ed. Quality Improvement Manual in Anatomic Pathology. Northfield, Ill.: College of American Pathologists; 1993.
2. Joste NE, Crum CP, Cibas ES. Cytologic/histologic correlation for quality control in cervicovaginal cytology. Experience with 1,582 paired cases. Am J Clin Pathol. 1995;103:32-34.
3. Tritz DM, Weeks JA, Spires SE, et al. Etiologies for non-correlating cervical cytologies and biopsies. Am J Clin Pathol. 1995;103:594-597.
4. Jones BA, Novis DA. Follow-up of abnormal gynecologic cytology. A College of American Pathologists Q-Probes study of 16,132 cases from 306 laboratories. Arch Pathol Lab Med. 2000;124:665-671.
5. Herbert A, Johnson J, Patrick J. Achievable standards, benchmarks for reporting and criteria for evaluating cervical cytopathology. Cytopathology. 1995;6:301-303.
6. Brown FM, Faquin WC, Sun D, et al. LSIL biopsies after HSIL smears. Correlation with high-risk HPV and greater risk of HSIL on follow-up. Am J Clin Pathol. 1999; 112:765-768.
7. Diaz-Rosario LA, Kabawat SE. Performance of a fluid-based, thin-layer Papanicolaou smear method in the clinical setting of an independent laboratory and an outpatient screening population in New England. Arch Pathol Lab Med. 1999;123:817-821.

Emily E. Volk, MD
Staff pathologist
St. John Hospital

George Birdsong, MD
Director of Cytology
Emory University School of Medicine
Grady Hospital

Diane D. Davey, MD
Director of Cytology
University of Kentucky

Drs. Volk and Birdsong are members of the CAP Cytopathology Committee.
Dr. Davey is chair of the CAP Cytopathology Committee.

Q.  A donation made by a blood donor two years ago tested positive for cytomegalovirus. The same donor donated blood recently, and it tested negative for CMV. Is it acceptable to label the current donation as CMV negative and provide the nonleukoreduced red blood cells from that donation to fill a physician’s order for CMV-negative red blood cells?

A.  Confirmed positivity results in permanent deferral from donation for most infectious disease tests performed on donated blood. This is based on the assumption that someone who has been infected by an agent may be chronically infected and thus a life-long risk to a recipient of his or her blood. For example, although failure to clear HBV occurs in less than five percent of Americans infected, our inability to readily distinguish these persons leads to permanent deferral of donors found positive for hepatitis B surface antigen. CMV often, if not always, establishes a chronic presence in an infected person through insertion of its genome into leukocytes’ genomes. Although false-positive results undoubtedly occur, a reactive test for CMV antibodies should be taken as an indication that the donor has been infected with CMV and may be able to transmit the infection through his or her leukocytes.

One cannot count on the continued presence of CMV antibody to identify infected persons because the health of the person and the season of the year can cause seroreversions.1 In fact, serostatus is a poor indicator of prior exposure to CMV since it is well established that more than one percent of seronegative donors can transmit CMV,2 and CMV can be recovered in culture from its genome identified in the blood of a sizable proportion, possibly a third to a half, of healthy, seronegative individuals.3,4

Thus it would be wise to regard donors found positive for CMV antibodies always to be at risk of transmitting this virus. However, with the advent of universal leukoreduction and the equivalent, if not superior, ability of this technique to produce CMV-reduced risk components, the need for CMV antibody screening should disappear.

1. Dumont LJ, Luka J, VandenBroeke T, et al. The effect of leukocyte-reduction method on the amount of human cytomegalovirus in blood products: a comparison of apheresis and filtration methods. Blood. In press.
2. Bowden RA, Slichter SJ, Sayers M, et al. A comparison of filtered leukocyte-reduced and cytomegalovirus (CMV) seronegative blood products for the prevention of transfusion-associated CMV infection after marrow transplant. Blood. 1995;86: 3598-3603.
3. Larsson S, Soderberg-Naucler C, Wang FZ, et al. Cytomegalovirus DNA can be detected in peripheral blood mononuclear cells from all seropositive and most seronegative healthy blood donors over time. Transfusion. 1998;38:271-278.
4. Taylor-Wiedman J, Sissons JG, Borysiewicz LK, et al. Monocytes are a major site of persistence of human cytomegalovirus in peripheral blood mononuclear cells. J Gen Virol. 1991;72: 2059-2064.

James P. AuBuchon, MD
Department of Pathology
Medical Center
Lebanon, NH

Vice chair, CAP Transfusion
Medicine Resource Committee