The cytological appearance of endocervical crypt involvement by high grade CIN has been described by Selvaggi and is similar in both conventional and liquid-based cervical cytology preparations [22, 23].

Exfoliated cells from crypts involved by high grade CIN may present one of two patterns. The type A pattern designated by Selvaggi consists of oval clusters of abnormal cells with smooth cell or slightly irregular borders in which the cells at the periphery are flattened or disorganised and those within the centre totally disorganised often with a spindling or whirling arrangement, in contrast to the residual honeycomb pattern of CGIN; the constituent cells show an increased nuclear/cytoplasmic ratio and hyperchromatic nuclei with granular chromatin (Fig. 6.9). The type B pattern consists of sheets of columnar cells with peripheral palisading and nuclear pseudostratification, suggestive of CGIN, but with nuclear features of squamous differentiation. The latter is characterised by evenly distributed chromatin or chromatin clumping and clearing, variation in size and shape of peripheral nuclei, irregularity of nuclear outlines with occasional notches and micronucleoli, which contrasts with the “salt and pepper” pattern of chromatin, relatively uniform nuclear size, shape and outline, and prominent nucleoli in neoplastic endocervical cells. Furthermore if palisaded or pseudo-stratified cells are present at the periphery of groups of cells derived from crypts involved by CIN, the cytoplasm is usually intact and dense with smooth edges and does not show the wispy cytoplasmic tags typical of CGIN (Fig. 6.10). Apoptosis and mitoses are clearly visualized in both entities and do not permit reliable distinction.

In many women with cervicitis or a benign endocervical polyp, cytology samples are entirely normal but in some cases endocervical cells may show reactive changes consisting of crowded cell groups with dense cyanophilic or eosinophilic cytoplasm, maintenance of internuclear spacing, anisonucleosis in round or ovoid nuclei, hyperchromasia and prominent nucleoli [12, 24, 25] (Fig. 6.11).

Occasionally polypoid tissue fragments from endocervical polyps appear in cervical cytology samples, comprising an inner core of numerous small dark stromal cells, covered by a layer of columnar cells with basal nuclei and tissue fragments from lower uterine segment polyps, which typically have a low gland to stroma ratio, present as small vessels running in various directions connected by thin sheets of small ovoid cells with indistinct cytoplasm [26].

Microglandular hyperplasia, as described below, is sometimes seen in cytology samples from a polyp.

Although spontaneous endometriosis of the cervix has been described, it is uncommon unless there has been a previous operative procedure such as a loop or cone biopsy or trachelectomy, superficial endometriosis then resulting from direct implantation at the site of injury during a subsequent menstrual period; alternatively endocervical brush samplers or spatulae with elongated tips may directly sample the lower uterine segment and harvest endometrial glands and stroma as intact tissue fragments [24, 27–35].

In conventional and liquid based cervical cytology samples, endometrial cells from the cervix are well preserved and are arranged in large sheets or strips showing gland openings and nuclear stratification respectively composed of cuboidal cells with a high nuclear/cytoplasmic ratio, relatively hyperchromatic nuclei with irregular contours and coarse chromatin; prominent nucleoli and mitoses may be found (Fig. 6.12). These features, together with the exfoliation pattern described, carry the risk that the cells may be mistaken for dyskaryotic endocervical cells. The latter cells, however, typically present as sheets of monotonous cells with crowded overlapping nuclei and the sheets have more striking architectural abnormalities.

Endometrial stromal cells may also be present, either in loose groups with ragged edges or admixed with the epithelial cells. Stromal cells are oval or round with rounded or reniform nuclei and scanty ill-defined cytoplasm, which is more abundant during the secretory phase of the cycle. The presence of stromal cells enables the diagnosis of endometriosis to be made [24, 28]. In conventional smears in particular the specimen may also be heavily blood stained. Directly sampled tissue from the lower uterine segment consists of tubular structures with well demarcated outlines composed of small uniform cuboidal cells with a peripheral rim of elongated delicate stromal cells orientated along the long axis of the tubular structure; these characteristic features are readily identified at low power routine screening magnification. Such structures are often likened to “elephant trunks” (Fig. 6.13).

Tubal metaplasia refers to replacement of epithelium at Mullerian-derived sites, such as the endometrial cavity or endocervix, by benign epithelium resembling that of the fallopian tube; in addition, tubal metaplasia frequently includes cells of endometrial type, so-called tuboendometrioid metaplasia. Tubal metaplasia has been found in between 31 and 100 % of adequately sampled cervices removed for both neoplastic and non-neoplastic reasons and tubal or tuboendometrioid metaplasia has been reported in 26 % of cervices removed after cone biopsy [27, 36–38].

Tubal and tuboendometrioid metaplasia tends to be multifocal and involve upper endocervical crypts rather than the lower endocervix and surface epithelium. Therefore it is more likely to be encountered in cervical cytology specimens following the use of brush devices for liquid based cytology sampling [38, 39]. Endometriosis may also occur in the same group of patients, as already described, although it is a less frequent event.

Although not thought to be preneoplastic, it is important that the cytological appearances are recognized and not misinterpreted as indicating endocervical glandular dysplasia: in one study tubal metaplasia accounted for the smear appearances in 76 % of cases in which endocervical glandular dysplasia had been suggested [40].

The cytological appearances in both conventional smears and liquid based preparations have been described in detail [39, 41–43]. All three cell types found in normal fallopian tube epithelium should be present, namely ciliated cells, secretory non-ciliated cells and intercalary cells. Although the proportion of these cells varies greatly between individual samples, ciliated columnar cells with apical terminal bars are necessary for the diagnosis and typically present as aligned groups of cells with well demarcated cytoplasm, which contrasts with the pseudostratified edge, bare nuclei and tapering cytoplasm of AIS (Fig. 6.14).

The cells, which are smaller than endocervical cells, may be arranged in flat sheets, three-dimensional clusters, small poorly cohesive groups or occur singly. Their nuclei, which are oval, round or elongated and are usually basal in position, tend to be larger than those of endocervical cells and evenly spaced with finely granular nuclear chromatin which is slightly darker than that of endocervical cell nuclei. Nucleoli are more often visible in LBC preparations and are small and single.

Intercalary cells, exclusive to tubal metaplasia but less readily identified in cytology samples, have triangular dark staining nuclei and little cytoplasm, in contrast to the other cells which have varying amounts of granular or vacuolated cytoplasm. Mitoses are rare.

The differential diagnosis includes cervical endometriosis, endometrial cells from the lower uterine segment, microglandular and reserve cell hyperplasia, ‘reactive’ endocervical cells, and dyskaryotic cells from CIN 3 involving endocervical glands. Cilia are usually a feature of benign endocervical cells although a solitary case has been reported of histologically confirmed ciliated adenocarcinoma of the cervix with prior liquid-based cervical cytology showing atypical, ciliated glandular cells that initially raised the diagnostic consideration of tubal metaplasia [44].

The cytological appearances of microglandular hyperplasia reflect the histological appearances described in Chap.​ 2 and are characterised by bidimensional or tridimensional cellular clusters made up of cubic or cylindrical glandular cells with vacuolated cytoplasm; basaloid cells with dense cytoplasm, corresponding to immature squamous metaplasia; and subcylindrical reserve cells with small, round nuclei and scant cytoplasm. The clusters also show microlumina or fenestrated spaces, preserved polarity and absence of nuclear peripheral dispersion [45] (Fig. 6.15). Microglandular hyperplasia is a very common condition but is only likely to cause cytological confusion with endocervical or endometrial neoplasia in the most florid papillary forms [39, 46–48].

Interpretative problems may arise during pregnancy if the endocervical glandular epithelium undergoes the type of extreme hypersecretory activity known as Arias–Stella change; it can also occur in other hyperprogestational states such as gestational trophoblastic disease and with high dose progestogen or ovulation inducing therapy [49].

The cytological features have been described in single case reports, and in one of these the cervical Arias-Stella reaction was associated with a cervical pregnancy [50, 51]. The atypical glandular cells occur singly, in syncytial clusters and cohesive sheets and are characterised by cyto- and karyomegaly, a high nuclear to cytoplasmic ratio, round to oval nuclei with finely granular or smudgy chromatin imparting a ground glass appearance, frequent intranuclear inclusions, and vacuolated or dense variable staining cytoplasm. Arias-Stella cells may be misinterpreted as malignant glandular cells if the history of pregnancy is not known [52].

Although the cytological changes in cervical squamous cells after radiation therapy have been well described, the literature on the alterations in endocervical cells in response to radiation therapy is very limited. Frierson et al. studied the effect of radiation therapy for cervical cancer on endocervical cells in brush specimens at various times following treatment. Endocervical cells appeared as single cells or clusters lacking the honeycomb appearance of normal endocervical cells with lavender, mucin-filled cytoplasm. In samples taken within 6 months of treatment, the majority of endocervical cells were enlarged but usually had a normal nuclear/cytoplasmic ratio although the nuclei varied in size and had coarse chromatin, large nucleoli and were frequently multinucleated. Repair cells and multinucleated histiocytes were seen in 83 and 61 % of samples, respectively. Each of these cytological findings was less apparent in follow-up smears taken more than 6 months after the completion of radiotherapy. Awareness of these cytological changes in endocervical cells after radiation therapy should prevent the overdiagnosis of cancer in follow-up endocervical brush specimens [53] (Fig. 6.16).