The prototypical cervical glandular neoplastic lesion is adenocarcinoma in situ (AIS) of the usual type. In the British literature, AIS has also been named “high-grade cervical glandular intraepithelial neoplasia” (HG-CGIN). These terms are now considered synonyms in the newest WHO classification system, which also includes stratified mucin-producing intraepithelial lesion (SMILE) as a variant of AIS/HG-CGIN [19]. AIS was originally described in 1953 by Friedell and McKay, and its histological features were recognized at that time [20]. The cytological morphology was described much later in the 1970s and 1980s [21–23]. There is significant evidence that AIS is a true precursor lesion to invasive carcinoma. AIS has a mean age which is reported to be from 12 to 18 years earlier than that of invasive endocervical adenocarcinoma [22, 24–26]. AIS is also more prevalent than invasive carcinoma indicating a larger pool of AIS from which only a portion goes on to develop invasive disease. AIS shows diffuse p16 immunostaining completely analogous to invasive carcinoma indicative of a neoplastic transformation of the epithelium and is positive for hrHPV of similar types to those seen in invasive endocervical cancer [27, 28]. In addition, areas of AIS are very commonly found adjacent to invasive endocervical adenocarcinomas. The usual type of AIS, in parallel with its invasive counterpart, is by far the most common in situ adenocarcinoma of the endocervix. In comparison to the other recognized in situ adenocarcinoma variants, namely, endometrioid and mucinous, the usual type constitutes more than 90% of all cases. AIS is generally not visible on colposcopic examination and may not be associated with symptoms or have only minor symptoms such as abnormal vaginal discharge [29, 30]. It is therefore most commonly identified via Pap or hrHPV testing [31–33]. Pap testing (as described below) can show diagnostic features of AIS but just as commonly shows atypical glandular cells which may be insufficient for a definitive interpretation of AIS. This equivocal finding is recognized to be very important for patient management and has been well incorporated into current management guidelines [34]. All cases of atypical glandular cells on a Pap test should prompt a colposcopic examination and histological sampling of the endocervical canal. Recent improvements in Pap test sampling device technology, which have allowed greater sampling of the endocervical canal and better recognition of the diagnostic cytological features, are thought to be the reason for the increased prevalence of AIS discovered today in screening programs. hrHPV testing is also sensitive for AIS; however, the specificity is less than with Pap testing because of the high prevalence of benign hrHPV infections in the background population. AIS most often grows in a contiguous fashion, and therefore during excisional procedures, clear margins do generally indicate complete removal [35]. However, rare examples of discontinuous AIS have been reported, and clinical follow-up following excision is necessary. Because virtually all AIS of the usual type is associated with hrHPV types, testing for hrHPV can be helpful in assessing residual disease following excision. Fortunately, complete excision of AIS is curative.

The usual type of invasive endocervical adenocarcinoma, just as in its correlate precursor lesion, is the most common type of cervical adenocarcinoma. It generally is recognized as comprising 80–90% of all adenocarcinomas, although several recent reports have shown that in Japanese populations, mucinous adenocarcinomas of gastric type may comprise as much as 30% of the total [40]. As in AIS, early superficially invasive adenocarcinomas may present with no symptoms, or occasionally with only minor symptoms, such as abnormal discharge or bleeding. In this early stage, Pap or HPV testing is most likely to show the only abnormal initial findings. Colposcopy may show areas of abnormality when the lesion occupies the lower portion of the endocervical canal. In larger tumors, symptoms of abnormal bleeding are almost always present and lesions are grossly visible on colposcopic examination. In larger tumors, the Pap test nearly always shows abnormality which may be present as either a diagnostic appearance of carcinoma or as atypical glandular cells.

The prognosis of invasive cervical adenocarcinoma is dependent on stage at presentation, with low stage disease generally having a good (curative) outcome (Tables 8.2 and 8.3). Most studies have shown that stage for stage cervical adenocarcinoma has a worse prognosis than squamous cell carcinoma [41–45]. Differences in dissemination and recurrence have been found for endocervical adenocarcinoma versus squamous cell carcinoma. Ovarian metastases are more common in endocervical adenocarcinoma than in squamous cell carcinoma [46]. Higher rates of distant metastasis have also been noted for endocervical adenocarcinoma [42, 47].

p16 immunohistochemistry is a useful marker for the presence of a true endocervical neoplastic lesion of the usual type. Virtually all usual type AIS and invasive endocervical adenocarcinomas are hrHPV positive and will show aberrant accumulation of p16. There are caveats for interpretation of this stain however. A positive stain should only be considered one in which the entire epithelium is diffusely positive, most often with both nuclear and cytoplasmic staining (Fig. 8.19a). This is important because several of the benign mimics noted below, such as tubal metaplasia and endometriosis, can show incomplete spotty, but sometimes strong staining for p16 (Fig. 8.19b). A marker of increased cellular proliferation (Ki67 or Mib1) can be supportive of a neoplastic process in conjunction with p16; however, studies have shown that Ki67 adds little predictive value to the p16 assay (Fig. 8.19c). Another marker IMP3 has been shown to be more specific for AIS with diffuse staining of most usual type glandular neoplasias with little staining reported in benign processes [48].

Immunohistochemistry can be useful in distinguishing endocervical from endometrial neoplasms, particularly when the lesions are large and extend to both cervix and corpus or are present in metastatic sites. Endocervical carcinoma is diffusely p16 positive, whereas endometrial cancer is typically only focally positive. Additionally, endocervical neoplasia is positive for CEA and negative for estrogen receptor and vimentin. Endometrial neoplasia is negative for CEA and positive for estrogen receptor and vimentin [49]. Both origins are most often positive for PAX8.