The Pap test was implemented for detection of cervical squamous cell carcinoma and proved to be the most successful cancer screening test in the history of medicine. It dramatically decreased the incidence of cervical cancer in regions where it was utilized. However, most developed countries internationally have recorded increasing rates of adenocarcinoma and adenocarcinoma in situ (AIS) over the past 20 years. In the U.S. there has been an overall decrease of 36.9% in all invasive cervical cancers over the 24-year period of 1973 to 1996; however, the change in age-adjusted incidence rates for adenocarcinoma was an increase of 29.1% over the same time period. Various factors preclude us from adequately identifying precursor lesions of adenocarcinoma.

 (1) Sampling- tends to be problematic as glandular lesions typically occur deep within endocervical glands, buried in the transformation zone and covered by metaplastic epithelium, high in the endocervical canal or masked by squamous disease.  Glandular disease is usually unifocal but maybe multifocal and can be associated with concurrent squamous neoplasia in up to 50% of cases. Due to its rarity compared to squamous neoplasia, colposcopists do not have extensive experience in recognizing these relatively uncommon lesions. 

(2) Biology- unlike in squamous disease, there is no well-defined or well-recognized low grade equivalent of LSIL in glandular disease and it is detected when high grade (adenocarcinoma in situ(AIS) or CGIN). Hence there are lesser opportunities for intervention prior to invasion.

(3) Cytology - glandular lesions are infrequently encountered in cytology, being reported in approximately 0.05% of all Pap tests, leading to diagnostic unfamiliarity and interpretative challenges. Interpretative difficulties are further compounded by AIS patterns that overlap with reactive endocervical cells, HSILs, endometrial cells, and tubal metaplasia. In 2001, the Bethesda System introduced AIS as a distinct interpretation category due to increased experience with recognizing its cytologic features. The reporting of atypical glandular cells (AGC) was also clarified in 2001, encouraging its sub-classification as to the cell type (endocervical/endometrial) and level of concern for neoplasia (favor neoplasia/NOS) in an effort to guide post-colposcopic management. The higher risk of subsequent neoplasia in AGC compared to ASC was emphasized in both reporting and management guidelines. As a rule of thumb, follow up of AGC is more often HSIL or benign entities rather than glandular neoplasia. The College of American Pathologists interlaboratory comparison and web based Bethesda interobserver reproducibility data confirm that cytology has a much higher false negative rate for glandular lesions compared to squamous lesions, involving both locator and interpretation errors.

(4) Histology: Endocervical adenocarcinomas can be classified into two main types of tumors, namely, those related to hrHPV representing the vast majority, and referred to as endocervical adenocarcinomas of usual type and those that are HPV negative and dominated by the gastric-type mucinous adenocarcinomas. Commonly encountered diagnostic problems concerning these endocervical adenocarcinomas include: (a) diagnosing invasion for endocervical adenocarcinomas of usual type, particularly superficial forms which must be distinguished from extensive endocervical AIS (b) distinguishing HPV related endocervical adenocarcinomas from endometrial endometrioid carcinomas; and (c) distinguishing benign/hyperplastic mucinous endocervical glandular proliferations from gastric-type mucinous endocervical adenocarcinomas, particularly minimal deviation adenocarcinoma. Immunohistochemistry can be key in some of these differential diagnostic considerations.

(5) HPV Testing and Cotesting- although most cervical AC is attributable to HPV, a greater proportion of cervical ACs is HPV negative when compared with squamous carcinoma. It is also important to consider that some cervical AC variants, endometrial AC, and ACs from other sites are not attributable to HPV. Taking these facts into consideration, it is reasonable to expect that HPV screening alone may be less sensitive for detection of AC. Cotesting will likely maximize detection of glandular abnormalities.

(6) Automation and molecular markers, including p16 immunochemistry have potential to improve detection of glandular neoplasia.

(7) Management- It is imperative that a diagnostic excision procedure be done for a cytologic interpretation of AIS/ Atypical endocervical cells favor neoplasia, since initial follow up colposcopy/ECC/biopsy are often negative.

(8) HPV vaccination- or primary prevention of cervical adenocarcinoma holds the most promise for decreasing its incidence worldwide.