Subcategorization of Papanicolaou Tests Diagnosed as Atypical Squamous Cells of Undetermined Significance

In this issue of the Journal, Renshaw et al1 address the issue of subcategorizing Papanicolaou (Pap) tests diagnosed as atypical squamous cells of undetermined significance (ASCUS). I would like to make several comments about this article in light of the recommendations presented on the Web site of the 2001 Bethesda System Conference2 and in light of ancillary studies, such as human papillomavirus (HPV) testing. One of the recommendations from the 2001 Bethesda System Conference is for changing the terminology of Pap tests formerly called ASCUS (using the 1991 Bethesda System terminology).2,3 The 1991 Bethesda Committee recommended that ASCUS Pap tests could be subclassified as favor reactive or favor dysplasia (favor low-grade squamous intraepithelial lesion [SIL]), and if neither of these categories seemed to fit, then the Pap test could be diagnosed simply as ASCUS (which some prefer to term the not otherwise specified [NOS] category).3 The 2001 Bethesda Committee recommended eschewing previous ASCUS terms for the term atypical squamous cells (ASC); all Pap tests then should be subclassified as either atypical squamous cells– undetermined significance (ASC-US) or atypical squamous cells–high-grade dysplasia not excluded (ASC-H).2 Note the differences in the 1991 and the 2001 Bethesda Systems categories of ASCUS. It was argued that the ASCUS, favor reactive category be eliminated from the 2001 schema because follow-up reveals that the majority of women with this diagnosis do not have a high-grade dysplasia but have a benign lesion.2 The ASCUS, NOS and ASCUS, favor dysplasia categories were collapsed into 1 category because it was thought that both categories included women with a significant risk of having dysplasia (mostly low grade) on follow-up. Although the risk of dysplasia associated with the categories of ASCUS, NOS and ASCUS, favor dysplasia are different, this difference in risk was not considered disparate enough to warrant 2 categories. Followup data for women with ASC-H show that the risk of having dysplasia, and particularly high-grade dysplasia, is significantly higher than for women with ASC-US.2 Atypical cells classified as ASC-H usually are metaplastic, and it is interesting to note that the 1991 Bethesda Committee recognized these cells as potentially representing a high-grade dysplasia.3 As a result of these recommendations, the 1991 Bethesda System category of ASCUS morphed from 3 categories to 2 categories, one predominantly a risk category for low-grade dysplasia and the other predominantly a risk category for high-grade dysplasia. The ASCUS categories examined by Renshaw et al1 are a hybrid of the 1991 and the 2001 Bethesda categories. The 1991 ASCUS, favor reactive category is maintained; the 1991 ASCUS, favor dysplasia and ASCUS, NOS categories are not collapsed; and the 2001 ASC-H category is added. Using receiver operating characteristic curve analysis, Renshaw et al1 argued that the sensitivity of the Pap test is lowered if any ASCUS subset is eliminated. Does this mean that the 2001 Bethesda Committee is mistaken in eliminating ASCUS, favor reactive and in collapsing ASCUS, NOS and ASCUS, favor dysplasia? I believe that the 2001 Bethesda Committee is justified in its recommendations, although I agree with Renshaw et al1 that removal of ASCUS subcategories decreases Pap test sensitivity. Before discussing these points further, the data and methods of Renshaw et al1 first deserve some comment. The data used in their analysis suffer from sample bias. The