Cytologic specimens judged as “suspicious for malignancy” are characterized by moderate to severe degrees of architectural disarray manifested by loss of cellular and architectural polarity (Figs. 7.3, 7.4, and 7.5). The honeycomb pattern found in sheets of benign epithelium is lost and replaced by groups and sheets of epithelial cells showing marked nuclear crowding, nuclear overlapping, and even cell in cell arrangements (Fig. 7.6). The presence of nuclear molding (Fig. 7.7) indicates a significant loss of polarity and appropriately assigns the specimen to the “Suspicious for Malignancy” or to the “Malignant” category depending on whether or not other significant features of malignancy are present. When cell groups are seen from the side, the normal picket fence-like arrangement with basally oriented nuclei is lost and replaced by cuboidal or columnar cells showing significant stratification of nuclei and distribution of nuclei into the mid or even upper thirds of the cells (Fig. 7.8). While loss of architectural and cellular polarity may be seen in reactive change and specimens assigned to the “Atypical” category, they are demonstrably more severe and more widespread in specimens assigned to the “Suspicious for Malignancy” category.

Cytologic specimens described as “suspicious for malignancy” are characterized by significant anisonucleosis (Figs. 7.8 and 7.9). A threefold or greater variation in nuclear size within any single cell cluster is characteristic of these specimens. Rare cell groups with greater than fourfold nuclear size variability may be seen, but when this degree of nuclear size variability is common, the specimen is more appropriately designated as “Malignant.”

Cells designated as “suspicious for malignancy” are characterized by prominent nucleoli (Fig. 7.10). Macronucleoli are not uncommon in these specimens. Chromatin patterns are characterized by clumping and coarsening. As seen in clearly malignant specimens, chromatin clearing can be seen in specimens designated as “suspicious for malignancy.” Nuclear membrane irregularities are often prominent (Fig. 7.1). Nuclear molding is occasionally seen (Fig. 7.7), but when present in more than a rare cell group, it is more appropriate for the specimen to be assigned to the “Malignant” category. An important characteristic of cells assigned to the “Suspicious for Malignancy” and “Malignant” categories is an increase in the nuclear cytoplasmic ratio. Both categories are characterized by cells with a significant nuclear to cytoplasmic ratio increase (Fig. 7.11). A definitive threshold for the nuclear cytoplasmic ratio in separating “suspicious for malignancy” from “malignant” does not exist. The presence of cell balls, papillary fragments, cell-in-cell arrangements, and a tumor diathesis favors a diagnosis of “malignant” rather than “suspicious for malignancy” . With the exception of the presence of a tumor diathesis, the presence of the other architectural features, when seen only rarely, is not definitively diagnostic of malignancy.