Cytologic specimens categorized as “Atypical” demonstrate cytologic and architectural aberrations greater than that clearly recognizable as reactive atypia, but less than that characteristic of those associated with the category “Suspicious for Malignancy”. Characteristically, there is a loss of architectural polarity exemplified by a mild alteration of the honeycomb pattern in the epithelial sheets and nuclear crowding with minor degrees of nuclear overlapping. This results in a pattern that mimics the drunken honeycomb typical of adenocarcinoma. (Fig. 4.1). While nuclear crowding is present within the epithelial sheets, cell balls with marked nuclear overlap obscuring underlying nuclei are not seen and true nuclear moulding is absent. Strips of cells are seen demonstrating a loss of nuclear polarity with nuclei haphazardly located throughout the lower two-thirds of the cell and are not restricted to the base (Fig. 4.2). A near-normal nuclear cytoplasmic ratio is maintained. The individual nuclei may show slight membrane irregularities (Fig. 4.3), but marked clefting and “rat bites” are not seen. Parachromatin clearing without other features of adenocarcinoma such a nuclear membrane abnormalities, 4:1 anisonucleosis and true “drunken honeycomb” render the cells as atypical (Fig. 4.4). Nucleoli are often enlarged but true macronucleoli are absent (Fig. 4.5). Minor degrees of anisonucleosis are present, but no single group of epithelial cells demonstrates greater than a twofold variability in nuclear size (Fig. 4.6). The smear background is either clean or contains red blood cells. Necrosis is absent. When “Atypical” changes are due to inflammation or a response to stones or stents, the nuclear features may be more abnormal with the presence of macronucleoli and substantial nuclear enlargement (Fig. 4.7). However, the nuclear cytoplasmic ratio remains within the normal range and inflammatory cells including neutrophils, lymphocytes, and plasma cells are characteristically present. Smears judged as “Atypical” demonstrate both architectural and cellular abnormalities but these do not reach the degree necessary to be considered major criteria for malignancy. In “Atypical” smears, fewer than three of the major criteria as defined by Nakajima et al. [24] are present. Cellblock preparations may help to appreciate the atypia as reactive (Fig. 4.8).