Endocervical and endometrial glandular cells may show a variety of cellular changes associated with various benign processes in the endocervical canal and endometrium [5]. Many of these reactive changes are not specific for any particular disease entity, but are of significance as mimics of glandular neoplasia in cervical cytology [6]. Reactive endocervical cells are characterized by the presence of a honeycomb or sheetlike arrangement with abundant cytoplasm, well-defined cell borders, and minimal nuclear overlap. Some degree of pleomorphism of cell size and nuclear enlargement may be noted; however, the nuclei remain round or oval with smooth contours and finely granular and evenly distributed chromatin. Nucleoli may be prominent, and multinucleation can occur, especially in cases of repair and inflammation. Cytoplasmic mucin may be diminished, giving the cell cluster a more hyperchromatic appearance. This constellation of reactive changes should be considered as “negative for intraepithelial lesion or malignancy” and not included in the AGC category (see Figs. 2.​4, 2.​32, and 2.​33) [1].

“Atypical endocervical cells” may be used for cases demonstrating some, but not all, of the criteria necessary for endocervical adenocarcinoma in situ (AIS) or invasive adenocarcinoma. These features may include nuclear enlargement, crowding, variation in size, hyperchromasia, chromatin heterogeneity, and/or evidence of proliferation. Some nonneoplastic processes that may show atypical cellular changes and lead to interpretive difficulty include lower uterine segment sampling, tubal metaplasia, repair, endocervical polyps, microglandular hyperplasia, Aria–Stella change, and effects of ionizing radiation [5, 7–10].

Vigorous sampling using an endocervical brush may transfer large hyperchromatic groups of intact normal endocervical cells to the slide, resulting in so-called brush artifact (see Fig. 6.8). Such hyperchromatic groups may cause concern due to the inability to visualize centrally placed cells. These groups should be carefully evaluated for nuclear and architectural features of glandular or squamous neoplasia before rendering an “atypical” interpretation.

Tubal metaplasia is usually categorized as “negative for intraepithelial lesion or malignancy” (NILM). However, it is also a significant pitfall in the interpretation of glandular changes [10]. Only when the findings are sufficiently atypical to raise concern for neoplasia should the interpretation “atypical endocervical cells” be used. The nuclei of cells from tubal metaplasia are often enlarged, hyperchromatic, and pseudostratified, resembling those features seen in endocervical adenocarcinoma in situ (AIS) (Figs. 6.12, 6.13, and 6.14). Although some architectural and cytologic features overlap with AIS, the nuclei in tubal metaplasia tend to be round or oval and display more finely granular, evenly dispersed chromatin. Feathered edges, rosette formation, and mitoses may be seen, but they are less common compared to classic AIS. The most helpful criterion is the presence of cilia or terminal bars that may require high-powered microscopic evaluation of cell clusters to be appreciated. Although the presence of rare ciliated abnormal cells has been described in glandular neoplasia, terminal bars and cilia are indicative of a benign origin in the vast majority of cases. In addition, intermixed goblet cells and slender “peg” cells may be identified in tubal metaplasia (see Figs. 6.14, 2.​19, 2.​20, and 2.​21) (Table 6.1). However, it must be remembered that because tubal metaplasia is very common in the high endocervical canal and lower uterine segment, it may coexist with endocervical neoplasia, and hence its presence should not dissuade an atypical or neoplastic designation if other types of atypical cells are present in the same specimen.

The 2012 consensus guidelines from the American Society for Colposcopy and Cervical Pathology (ASCCP) include recommendations for the initial workup and subsequent management of women with glandular abnormalities based on the 2001 Bethesda terminology [22].

Initial management of all categories of AGC, except atypical endometrial cells is colposcopy with endocervical sampling. Women 35 years and older or at risk for endometrial neoplasia should also have endometrial sampling. Those with atypical endometrial cells should have endometrial and endocervical sampling; colposcopy may be deferred if endometrial pathology is identified. Subsequent management of AGC depends on the findings from the initial sampling and cytologic interpretation. Triage using repeat cytology is not an option for the AGC category as it is high risk, and may harbor significant squamous and glandular preinvasive and invasive disease. If invasive disease is not identified on initial evaluation, a diagnostic excisional procedure is recommended for women with a cytologic interpretation of atypical glandular or endocervical cells, favor neoplasia or endocervical adenocarcinoma in situ.

The 2012 ASCCP guidelines do not recommend hrHPV triage for initial presentations of AGC. Based on two recent large studies from the United States, 25 % of cases in the AGC category test positive for hrHPV [23–25]. The most prevalent hrHPV genotypes detected are 18/45, followed by 16 [26, 27]. Overall, HPV genotype 16 and/or 18 accounts for 20–53 % of all AGC that are positive for hrHPV [26–28]. Few studies have addressed hrHPV positivity among the subcategories of AGC. Overall, approximately 50 % of AGC cases that test positive for hrHPV are found to be associated with significant lesions (e.g., HSIL, AIS or endocervical adenocarcinoma), whereas less than 5 % of AGC cases, which are negative for hrHPV, are found to be associated with significant HPV-associated precancer/cancer diseases [22, 23, 29]. In summary, hrHPV-positive AGC is more likely to have cervical pathology, such as adenocarcinoma in situ, endocervical adenocarcinoma, squamous intraepithelial lesion, or squamous carcinoma. hrHPV-negative AGC is more likely to show cancer which is endometrial or extrauterine in origin, or a benign reactive condition such as an endocervical or endometrial polyp.