Based on the Surveillance, Epidemiology, and End Results (SEER) Program data, Wang et al. demonstrated that adenocarcinoma accounts for approximately 20 % of all cervical carcinomas, but the cervical intraepithelial neoplasia 3 (CIN 3 ) to adenocarcinoma in situ (AIS) ratio is 34, suggesting a low incidence of AIS as a precursor of invasive carcinoma compared with CIN 3 [21]. In addition, they revealed that AIS to adenocarcinoma and CIN 3 to squamous cell carcinoma (SCC) ratios are 0.8 and 6.69, respectively [21]. The low incidence of AIS and higher incidence of its invasive counterpart may be explained by four possibilities:
Regarding common AIS types, in a series of early invasive adenocarcinomas, AIS was identified in up to 85 % of cases [22], and the time-to-progression to its invasive counterpart, ranging from 2 to 8 years, appears not significantly different from high-grade squamous intraepithelial lesion (HSIL) (CIN 2/3) [22–24], and therefore the latter two might be main sources of the low detection rate of AIS [25]. In the literature, however, there are cases of small invasive carcinoma without AIS, suggesting a rapid progression [22]. Information on the natural history of AIS is still limited, and thus, in cases of uncommon subtype of AIS, a variety and combination of factors may be considered.

AIS is defined as an intraepithelial lesion containing malignant-appearing glandular epithelium that carries a significant risk of developing into invasive adenocarcinoma if not treated [1]. By definition, desmoplastic stromal reaction indicating destructive invasion is absent in cases of AIS, although intraglandular tufting or cribriform growth may be seen. In the literature, Friedell and McKay first described AIS in 1953 [26], and thereafter the lesion has been widely accepted as a precancerous lesion. The rationale indicating the precancerous nature of AIS includes:
Clinically, AIS is commonly asymptomatic and is mostly detected by screening. Patient age varies from 18 to 75 with a mean age of 35 in one large study [27]. The incidence varies, e.g., 1 in 25,000–475,000 women, depending on race, geography, and socioeconomic status [36, 37].

In addition to the common usual type (endocervical type ) as described by Friedell et al. (Figs. 12.4 and 12.5) [26, 38], there are a variety of morphologic subtypes of AIS, including intestinal type [38] (Fig. 12.6), endometrioid type (Fig. 12.7) [38], clear cell type (Fig. 12.8) [39], serous type (Fig. 12.9), and tubal or ciliated type (Fig. 12.10) [40]. Gastric type of AIS (Fig. 12.11) has also been described [19]. The subclassification of AIS does not appear to have any impact on patient management, but pathologists are encouraged to be aware of the morphologic spectrum of AIS of the uterine cervix to avoid misinterpretation and in order to understand the histogenesis of cervical adenocarcinoma.

Microscopically, the usual type of AIS is typically located in the transformation zone with some exceptions. On low power view, it can be recognized by deeply stained columnar epithelium (Fig. 12.4a, b) because of moderate to marked nuclear enlargement, overlapping, and hyperchromatism (Fig. 12.4c), in contrast to the basally located small nuclei of normal glandular epithelium. Atypical columnar cells replace preexisting mucus-secreting columnar cells, and the contour of the endocervical glands is preserved. The atypical cells commonly extend from the superficial to the deeper portion of the glands and frequently show a clear front with preexisting nonneoplastic glandular epithelium (Fig. 12.4d). It should be kept in mind that AIS involving nonspecific endocervical glandular hyperplasia may show gland crowding, making early invasion a diagnostic concern. Therefore, the distribution and architecture of the background nonneoplastic glands should be considered, as well as the architectural complexity of atypical glands, desmoplastic stromal reaction, and inflammatory reaction. Although there is heterogeneity with respect to nuclear size and shape, the nucleolus is usually absent or small, and vesicular nuclei with conspicuous nucleoli and significant nuclear pleomorphism are rather indicative of invasive adenocarcinoma. The amount of intracytoplasmic mucin is also lower. Mitotic figures and apoptosis and the existence of the front formation are diagnostically important [41], and, in the absence of these features, pathologists should be careful and consider AIS mimics including tubal metaplasia as differential diagnoses. The characteristic front formation indicates that AIS arises de novo without a precursor lesion, which is biologically and morphologically intermediate between normal epithelium and AIS [42]. Approximately two-thirds of cases are incidentally found on biopsy or conization for HSIL (Fig. 12.5) [38].

The intestinal type AIS is characterized by an admixture of goblet cells (Fig. 12.6). Neuroendocrine cells that show immunoreactivity for chromogranin can be also identified, but Paneth-like cells are rarely seen. McCluggage et al. demonstrated CDX2 positivity in cases of intestinal type AIS, indicating the true enteric differentiation of this particular lesion. Nuclear abnormalities may be minimal, and therefore pathologists are encouraged to perform a diligent search when encountering a lesion interpreted as intestinal metaplasia since it may represent a neoplastic condition [43].

Endo metrioid type AIS is composed of cells with almost no intracytoplasmic mucin (Fig. 12.7). This type, like the tubal type, may be associated with tuboendometrioid metaplasia [40], and thus the associated invasive adenocarcinoma is located in the higher portion of t he endocervical canal away from the transformation zone [22].

Interestingly, Jaworski et al. examined AIS subtypes, and in their series, they found that endometrioid type more frequently coexists with usual type and/or intestinal type and is only occasionally found alone and that intestinal type is always in association with usual type and/or endometrioid type [38]. These results suggest possibilities that intestinal type AIS is derived from usual-type AIS and that the endometrioid type may be classified into two groups: HPV-negative de novo type and HPV-positive usual type-related; the latter might represent mucin-deficient usual type AIS.

Clear cell type AIS shows atypical cells with abundant clear or pale eosinophilic cytoplasm and hobnail appearance (Fig. 12.8). It imparts a close resemblance to the Arias-Stella reaction and thus can be a diagnostic pitfall, although, from a practical point of view, it may be better to think of a benign diagnosis in a pregnant woman.

Gastric type AIS is characterized by abundant clear or pale eosinophilic cytoplasm and enlarged vesicular nuclei with conspicuous nucleoli (Fig. 12.11). Lobular endocervical glandular hyperplasia (LEGH) with intraepithelial carcinoma (atypical LEGH) is distinguished from this condition by its characteristic lobular architecture, but both of these conditions might be GAS precursors [19]. It should be kept in mind that the nuclear abnormalities in cases of gastric type AIS may be very unremarkable and thus can be overlooked without familiarity of its cytologic features. Immunohistochemically, this type is positive for HIK1083 and MUC6, which are representative gastric markers [19]. Occasionally, it can be positive for p16^INK4a [19], suggesting an implication of high-risk HPV, but this remains undetermined.