A variety of benign changes can occur in the endocervix which enter into the differential diagnosis when a glandular lesion is suspected on cervical cytology. Before delving into the cytology, a general understanding of the histology of benign lesions is helpful (Table 5.1) [1].

Tubal and tubo-endometrioid metaplasia (TEM) refers to replacement of endocervical epithelial cells by ciliated cells, slender non-ciliated “intercalated” cells with apical snouts, and the mucinous “peg” cells similar to those of the fallopian tube or endometrial glands [2, 3]. This type of metaplasia is very common in the upper portions of the endocervical canal, particularly in the late childbearing age group (Fig. 5.1).

Superficial cervical endometriosis is recognized by the presence of endometrial glands accompanied by endometrial stroma. Endometriosis is often present just below the surface of the cervical squamous epithelium and may erode through the surface to be sampled in the taking of a Pap test (Fig. 5.2).

Oxyphil metaplasia of endocervical glands results in glands lined by a single layer of columnar cells with dense, eosinophilic, and focally vacuolated cytoplasm and enlarged slightly irregular nuclei (Fig. 5.3) [4]. This metaplasia is akin to the eosinophilic change noted in endometrium where it is thought to be a reaction to degeneration or breakdown.

Ectopic prostatic tissue has rarely been identified in the cervix [5–7]. The prostatic glands have a two-cell layer lining, flattened cells next to the basement membrane and columnar cells facing the lumen (Fig. 5.4). Most lesions are positive for prostatic-specific acid phosphatase and in many cases, prostatic-specific antigen. Recently an origin from Skene’s glands, the female equivalent of prostate glands, has been proposed [8].

Tunnel clusters are aggregates of endocervical glands lined by tall columnar epithelium which form rounded subsurface masses (type A) [9]. The glands may become cystic with more flattened epithelium (type B) (Fig. 5.5). Reactive atypia of the glandular epithelium may occur [10].

Microglandular hyperplasia (MGH) consists of closely packed small glands which are lined by cells showing distinctive subnuclear vacuoles (Fig. 5.6). MGH is often noted in endocervical polyps (ECPs) and is common in women treated with hormones such as contraceptives. Rarely, atypia in MGH may simulate carcinoma [11].

Endocervical glandular hyperplasia is rare and may occur either as a diffuse band-like proliferation of endocervical glands known as diffuse laminar endocervical glandular hyperplasia (DEGH) or as lobular endocervical hyperplasia (LEGH) (Fig. 5.7). DEGH is composed of a superficial band of tightly packed benign-appearing endocervical glands. LEGH is made up of a lobular arrangement of tightly packed glands showing pyloric gland metaplasia. Some have suggested that LEGH is a precursor lesion to mucinous endocervical adenocarcinoma.

Mesonephric hyperplasia is characterized by small round tubules lined by low cuboidal non-mucinous epithelium with dense intraluminal eosinophilic material (Fig. 5.8) [12, 13]. While the uncommon mesonephric remnants are most commonly found in the deep lateral wall of the cervix, the even less common mesonephric hyperplasia can extend throughout the cervical wall to the luminal surface [14–16].

Reactive atypia has been described in normal endocervical glands and surface glandular epithelium secondary to trauma, such as endocervical or endometrial curettage, infectious organisms, or radiation therapy (Fig. 5.9) [17].

Viral infections of the endocervical epithelium, especially with cytomegalovirus and Herpes simplex virus, can cause reactive atypia [18, 19].

Pregnancy may cause endocervical atypia, especially the Arias-Stella reaction (Fig. 5.10) [20].

Finally, endocervical atypia maybe found in ECPs, most likely secondary to traumatization of the surface of the lesion (Fig. 5.11) [21].

In addition to true reactive changes of the endocervical mucosa, endocervical sampling devices (brooms and brushes) that reach high into the canal and scrape large numbers of cells from the epithelium may cause diagnostic difficulties for cytologists. The presence of large aggregates of densely packed endocervical cells (the so-called hyperchromatic crowded groups (HCGs)) can lead to over interpretation as “atypical,” primarily because of the normal pleomorphism of native endocervical cells and because of the nuclear hyperchromasia associated with extreme cell overlap in such lesions.

Typical reactive changes in endocervical cells occur under a variety of circumstances, including trauma, infectious or inflammatory processes, and chronic irritation; however, the causes of these changes are often obscure. The nuclei can become alarmingly large. The usual nuclear size is about 8 μm in diameter but the nuclei can enlarge up to 15 or 16 μm with reactive changes [22]. Nucleoli may be present and slightly enlarged (Fig. 5.12). Multinucleation may occur (Fig. 5.13). The chromatin, however, remains bland and the nuclear contour is smooth.

In addition, features of repair may be present, especially in situations such as the presence of an ECP or MGH which may protrude from the surface of the cervix and thus be prone to trauma. Although both ECP and MGH have characteristic histologic findings, the cytologic changes are not specific. Epithelial repair presents as cell culture-like flat sheets of endocervical cells with well-defined cytoplasmic boundaries giving the sheet a cobblestone appearance (Fig. 5.14). The cytoplasm of the cells at the periphery of the groups may appear to be stretched, as if to cover an underlying breach in the tissue, and appendages of cytoplasm from the margins of the group gives a “taffy-pull” appearance. The cells generally tend to be well polarized and can have a streaming effect, sometimes described as a “school of fish” pattern. The nuclei in typical repair are uniformly enlarged with open, relatively pale chromatin, with one or more distinct nucleoli and occasional mitotic figures. Reactive/reparative changes are often seen in a background of inflammation and inflammatory cells are commonly found intermixed within the sheets of reparative epithelium (Fig. 5.15).