The term polyp simply refers to a protuberant mass of tissue. The tissue may be regenerative, inflammatory or neoplastic in origin; less often, it may be congenital or hamartomatous. In gynaecological practice, a cervical polyp is usually a benign polypoid overgrowth of the endocervical tissues possibly due to chronic inflammation, although other types of polypoid lesion are also encountered.

Cervical polyps of endocervical origin are common, occurring in approximately 5–8% of women, most of whom are multiparous and over the age of 40 years. The polyps are usually solitary, less than 3 cm across, asymptomatic, and often an incidental finding at the time of routine cervical cytology sampling. They may, however, cause vaginal discharge or bleeding. The presence of a polyp may also compromise cervical cytology sampling if overlying part of the transformation zone.

Histologically, they are composed of endocervical tissue covered by columnar, squamous or immature metaplastic epithelium and are often inflamed (Fig. 25.1). Microglandular endocervical hyperplasia may be present focally.

Fig. 25.1 Section of a benign endocervical polyp covered by endocervical and metaplastic epithelium. The stroma shows a light non-specific inflammatory cell infiltrate (H&E).

Although cervical intraepithelial neoplasia (CIN) is no more likely to be found in an endocervical polyp than in the native cervix and the incidence of adenocarcinoma or squamous carcinoma arising in a polyp is low (0.2–0.4%),¹ removal of cervical polyps, accompanied by curettage to exclude coexisting endometrial pathology, is generally advisable, particularly in symptomatic women.² Histological examination is imperative and may reveal that the polyp is in fact an unsuspected condyloma or a neoplasm.

Cytological findings: cervical polyps

• Cytology samples are usually entirely normal

• Endocervical cells may show reactive features.

Diagnostic pitfalls: cervical polyps

The cytology sample may be of poor quality if the polyp has significantly interfered with sample taking, caused bleeding or is associated with cervicitis. Sometimes, endocervical cells from the polyp show reactive changes including marked nuclear enlargement with pleomorphism, hyperchromasia and prominent nucleoli (Fig. 25.2). Occasionally, polypoidal tissue fragments from the polyp 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.³ If there are interpretative problems, the investigation should be repeated after removal of the polyp.

Fig. 25.2 (A) Endocervical cell cluster with reactive changes in cervical smear with a heavy inflammatory exudate. A cervical polyp was recorded in the clinical details. The smear was repeated after polypectomy and was found to be normal. The polyp showed non-specific inflammation (PAP). (B) Polypectomy specimen showed similar changes at the surface of the polyp (H&E).

Microglandular hyperplasia, as described in the previous chapter, is sometimes seen in cytology samples from a polyp. Human papillomavirus associated changes, squamous or glandular precancer or invasive neoplasia within a polyp, if appropriately sampled, yields the same cytological findings as described in the preceding chapters.

This term is used to describe polyps arising at or just above the junction of endocervix with endometrium. They typically have a low gland to stroma ratio. The cytological features of two such polyps presenting in cervical smears have been described.³ Both smears contained tissue fragments comprising small vessels running in various directions, connected by thin sheets of small ovoid cells with indistinct cytoplasm.

During pregnancy the cervical stroma frequently undergoes focal decidual change and this reaction may be so extensive as to form a polypoid protrusion of the cervical stroma known as a decidual polyp. The decidual change is typically subepithelial in location, often disrupting the overlying epithelium. The histological appearance may be misinterpreted as carcinoma since decidualised stromal cells have large nuclei, prominent nucleoli and abundant cytoplasm, imparting an epithelioid appearance (Fig. 25.3A).⁴

Fig. 25.3 (A) Decidual reaction in cervical stroma of a young woman at 10 weeks of pregnancy. The cervix had a clinically suspicious appearance and was biopsied to exclude a tumour. The stroma shows swollen pale cells with abundant cytoplasm, well-defined cell membranes and regular nuclei (H&E). (B) Decidual cells in a cervical smear taken from the same patient. The cells are similar to those in the biopsy, appearing swollen and pale against the background of neutrophil polymorphs (PAP).

(Courtesy of Professor B. Naylor, Michigan, USA.)

Interpretive problems may arise during pregnancy if the endocervical glandular epithelium undergoes the type of extreme hypersecretory activity known as Arias–Stella change. This has been observed in 9% of cervices from hysterectomy specimens obtained during pregnancy⁵ and is due to the action of human chorionic gonadotrophin. It can also occur in other hyperprogestational states such as gestational trophoblastic disease and with high-dose progestogen or ovulation-inducing therapy.⁶ Histologically, the cervix shows an exaggerated secretory pattern in the glands, associated with papillary infoldings of the epithelium, mirroring the findings in endometrium (see Ch. 26). The nuclei may be pleomorphic and hyperchromatic and the cytoplasm is vacuolated, producing a hobnail appearance at the cell surface. When superficial endocervical glands show Arias–Stella change it is possible for cells from these glands to be seen in a cervical smear.

Endometriosis refers to the presence of endometrial glands and stroma outside the body of the uterus. Cervical endometriosis is uncommon unless there has been a previous operative procedure, superficial endometriosis then resulting from direct implantation, as a response to injury, or as a metaplastic or neoplastic process (Fig. 25.4). In a study of 42 cervices from hysterectomies following conisation, Ismail reported the presence of endometriosis in 43% of cases.¹⁰ This ectopic tissue is hormonally responsive and friable and the patient may therefore present with irregular contact bleeding.

Fig. 25.4 (A) Endometriosis of cervix. The biopsy was taken from a haemorrhagic friable area at the external os in a middle-aged woman presenting with contact bleeding 9 months after diathermy to a prominent nabothian follicle. Note the cellular endometrial stroma surrounding irregular glands lined by darkly stained epithelium of endometrial type (H&E). (B) Endometrial cell group composed of crowded cells with hyperchromatic nuclei in a haemorrhagic background. Cervical smear is from the patient whose biopsy is shown in (A) (PAP).

Nabothian follicles or mucus retention cysts are cystically dilated endocervical crypts, which develop because the opening of the gland becomes occluded by inspissated mucus or metaplastic epithelium at the orifice of the crypt. If a follicle is ruptured while taking a conventional smear, streaks of mucoid inflammatory debris may be obtained (Fig. 25.5), associated with multinucleate cells having abundant foamy cytoplasm. While some of these cells are clearly histiocytes, others are endocervical in origin. Degenerate forms with pyknotic nuclei may be confused with dyskaryotic cells.

Fig. 25.5 Contents of a nabothian follicle in a cervical smear showing granular inflammatory debris mixed with thick mucoid material (PAP).

The term microglandular hyperplasia is applied to an alteration in endocervical glandular tissue frequently seen in pregnancy or during oral contraception and other hormone therapy. It is thought to be due to progestogen stimulation and does not appear to have any premalignant potential. Typically, there are one or more small polypoid areas arising from the endocervical canal but more extensive involvement of the endocervical epithelium also occurs. The microscopic features have been fully described in Chapter 24.

Malakoplakia is an uncommon chronic inflammatory condition usually involving the urinary tract but which can affect many other organs. It is thought to result from an acquired defect in macrophage function resulting in an inability to degrade ingested bacteria, particularly E. coli. It is often associated with primary or acquired immunodeficiency.

Malakoplakia of the female genital tract is rare, occurring most often in the vagina.¹⁴ The patient is typically elderly and presents with postmenopausal bleeding. Polypoid friable lesions may be seen in the vagina and on the cervix, simulating malignancy. Histologically, there is an infiltrate of histiocytes with abundant granular eosinophilic cytoplasm. Some of these cells contain the pathognomonic intracytoplasmic calcified laminated spherules known as Michaelis–Gutmann bodies and microorganisms may sometimes be demonstrated.

Single reserve cells, as described in Chapter 23, lie between the columnar endocervical cells and the basement membrane, predominantly in the proximal part of the endocervical canal. When they proliferate without maturing this is described as reserve cell hyperplasia. It is often seen in pregnant or postmenopausal women and in women using oral contraceptives, representing the earliest stage in the evolution of immature squamous metaplasia. It may also result from tamoxifen therapy.¹⁷

Histologically, there are several layers of small primitive cells beneath the columnar endocervical epithelium (Fig. 25.6A). The cells have round or oval nuclei, finely granular chromatin and ill-defined cell boundaries. Atypical reserve cell hyperplasia is thought to be capable of progressing to either CIN 3 or endocervical neoplasia, thus reflecting the bipotential role of the reserve cell.

Fig. 25.6 (A) Reserve cell hyperplasia in section of cervix. There is a multilayered row of immature cells beneath the tall columnar epithelium of the endocervical canal, showing no evidence of squamous metaplasia (H&E). (B) Reserve cell hyperplasia in cervical smear. This large cellular group of endocervical origin is more crowded than normal and shows many dissociated bare nuclei at the margins. The degree of crowding was thought suggestive of endocervical dyskaryosis, but biopsy showed reserve cell hyperplasia only (PAP).

Cytological findings: reserve cell hyperplasia

• Cells in sheets, clumps and pairs, and that are dissociated

• Little or no cytoplasm

• Nuclei are pale or normochromatic

• Columnar cells may be attached

• Anisocytosis, nucleoli and mitoses are found in atypical hyperplasia.

Hyperplastic reserve cells are typically shed in sheets and are also seen in rows with ramifications, in clumps, paired and single. Columnar endocervical cells may be attached to these cells, arranged in a single layer (Fig. 25.6B).

The reserve cells have oval, round or bean-shaped nuclei, slightly smaller than those of endocervical cells. One end of the nucleus may be pointed and there may be a longitudinal groove. Nuclear moulding is also a recognised feature. The chromatin is finely granular and a small nucleolus may be apparent. Most nuclei are naked when the cells are dissociated, although a small amount of poorly defined cytoplasm is occasionally present (Fig. 25.6B). Sheets of reserve cells typically have a syncytial appearance because cell borders are poorly defined.

Diagnostic pitfalls: reserve cell hyperplasia

In atypical reserve cell hyperplasia the cells show the same exfoliation pattern, but the nuclei show anisokaryosis which may be marked. The nuclear border is prominent and the chromatin is slightly granular but evenly dispersed (Fig. 25.7). The nuclei are normo- or hypochromatic rather than hyperchromatic. Nucleoli may be visible and mitoses can be seen. Atypical reserve cells are rarely seen in negative samples, tending to be present when dyskaryotic squamous or glandular cells are also present. The higher the grade of dyskaryosis the more likely is the finding of atypical reserve cells. They can usually be distinguished from dyskaryotic cells, which have denser cytoplasm and hyperchromatic nuclei.^18,19

Fig. 25.7 (A) Atypical reserve cell hyperplasia in cervical cone biopsy. There is a zone of multilayered reserve cells forming a cuff around most of the glands. The cells are crowded and disorganised in contrast to Figure 25.6A, but no mitoses are seen (H&E). (B) Atypical reserve cell hyperplasia in the cervical smear from the patient whose histology is illustrated in (A). Fragments of crowded small cells with hyperchromatic nuclei are seen, and were interpreted as severe glandular dyskaryosis. The cone biopsy showed CIN 1 in addition to the atypical reserve cell hyperplasia but no evidence of glandular intraepithelial neoplasia was found (PAP).

Tubal metaplasia refers to replacement of epithelium at müllerian-derived sites, such as the endometrial cavity or endocervix, by benign epithelium resembling that of the fallopian tube. It has been found in between 31% and 100% of adequately sampled cervices removed for both neoplastic and non-neoplastic reasons.^20–22 Tubal metaplasia frequently includes cells of endometrial type, so-called tuboendometrioid metaplasia (Fig. 25.8). Ismail has also reported finding tubal or tuboendometrioid metaplasia in 26% of cervices removed after cone biopsy.¹⁰

Fig. 25.8 (A) Tubal metaplasia in histological section of cervix. The endocervical gland lining consists of ciliated cells with slight multilayering imparting a more disorganised appearance than is usually seen in endocervical mucosa or glands (H&E). (B) Tuboendometrioid metaplasia of cervix showing two glands lined by cells with tubal and endometrial features, set in inflamed stroma (H&E).

The changes tend to be multifocal and involve upper endocervical crypts more commonly than the lower endocervix and surface epithelium: the findings are more likely to be encountered in cervical cytology specimens following the use of brush devices for LBC sampling.^22,23 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 recognised and not misinterpreted as indicating endocervical glandular dysplasia. In a study by Novotny and co-workers²⁴ tubal metaplasia accounted for the smear appearances in 76% of cases in which endocervical glandular dysplasia had been suggested.

Cytological findings: tubal metaplasia (Fig. 25.9)

• Numerous columnar cells, some ciliated and non-ciliated

• Large- to medium-sized sheets and clusters, and single cell arrangements

• Nuclei larger and darker than endocervical cells

• Intercalary cells may be recognised.

Fig. 25.9 (A) Tubal metaplasia in a group of glandular cells in a cervical smear taken as follow-up of treated CIN. There is a columnar border showing ciliated cells along the lower edge of the group. Intercalary cells cannot be identified (PAP). (B) Tuboendometrioid metaplasia in the same smear as shown (A). This group shows degenerative features with nuclear irregularities and crowding as seen in endometrial cells, although without the characteristic central core of stroma (PAP).

The changes in both conventional smears and liquid-based preparations have been described in detail.^23–28 The three cell types seen in fallopian tube epithelium should be present, namely ciliated cells, secretory non-ciliated cells and intercalary cells. Their proportion in a sample varies greatly, but ciliated columnar cells with apical terminal bars are necessary for diagnosis.

The cells are arranged in flat sheets, three-dimensional clusters, small poorly cohesive groups or they may occur singly. Cells are smaller than endocervical cells but nuclei tend to be larger and evenly spaced, although there may be overlapping of nuclei in the three-dimensional groups.

They are oval, round or elongated and are usually basal in position. The chromatin is finely granular and typically 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 yet not readily seen 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.

Diagnostic pitfalls: tubal metaplasia

The presence of aligned ciliated cells is one of the most helpful features in distinguishing tubal metaplasia from endocervical glandular dysplasia, although cilia are not often preserved in all groups in a sample. Rosettes, palisades of cells and the feathered appearance at the edge of sheets of cells typically seen in adenocarcinoma in situ (AIS) are rarely seen in tubal metaplasia. The nuclei are also different in AIS, since they tend to be elongated and hyperchromatic with coarsely granular chromatin and prominent nucleoli. They are invariably crowded and stratified and mitotic figures are usually present.

Other differential diagnoses include 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.

Occasionally, metaplasia on the ectocervix to a transitional type of epithelium has been identified in histological sections of the cervix, particularly in older postmenopausal women. This change causes no symptoms and its importance lies principally in the potential for a mistaken diagnosis of high-grade CIN in hysterectomy specimens because of the lack of maturation of cells in crowded epithelium.²⁹ However, careful examination of tissue sections reveals uniformity of nuclei, an even chromatin pattern and lack of mitotic activity, thereby excluding the possibility of neoplasia. No direct relationship to cervical pre-cancer or invasive disease has been established but a recent study has suggested that transitional cell metaplasia may be related to human papillomavirus infection.³⁰

Descriptions of the cytological findings when cells from this type of mucosa are sampled have been published. The finding of cohesive groups of cells containing streaming spindled nuclei with haloes, grooves, tapered ends and wrinkled contours permits distinction from squamous dyskaryosis.^30,31

Leukoplakia is a clinical concept describing the presence of white patches on the mucosa of the ectocervix or other areas of genital tract squamous epithelium. Typically, at the cervix, lesions are due to hyperkeratosis or parakeratosis of the ectocervical epithelium. The squamous mucosa may be atrophic or normal but is often hyperplastic and is covered by a thick layer of anucleate keratin (hyperkeratosis) or keratin in which pyknotic nuclei persist (parakeratosis). There is usually a well-defined granular layer beneath the layer of keratin.

These changes are often due to chronic irritation of the epithelium, for example, when there is uterine prolapse (Fig. 25.10A), if a pessary is in place or with severe chronic inflammation. Sometimes, however, the underlying epithelium is abnormal, showing evidence of HPV infection, CIN or invasive squamous carcinoma. Colposcopic examination is therefore appropriate if leukoplakia is present, even in the absence of dyskaryotic squamous cells in the cytology sample, to rule out serious underlying pathology.

Fig. 25.10 (A) Section of cervix from a case of uterine prolapse. The squamous mucosa is thickened and covered by a dense layer of keratin (H&E). (B) Hyperkeratosis in a cervical smear from a patient with procidentia. Much of the smear consisted of deeply stained anucleate squames from the keratinised surface of the cervix (PAP).

When cervical mucosa is ulcerated or damaged re-epithelialisation of denuded stroma occurs, initially by immature metaplastic epithelium, to be replaced later by mature squamous epithelium. Changes due to repair and regeneration may be seen in cases of severe cervicitis and cytology samples taken after cervical biopsy, ablative therapy, or irradiation.^32–34 The cells obtained can be confused with dyskaryotic squamous and glandular cells. It is therefore advisable to delay follow-up smears for at least 4 months and preferably for 6 months after treatment.

Features seen histologically include thickening of the squamous epithelium, basal cell hyperplasia and immature squamous metaplasia. The nuclei may be hyperchromatic and have prominent nucleoli but there is no nuclear crowding or overlapping and normal maturation of cells in the upper layers of the mucosa. Endocervical epithelium may also display similar reactive features with nuclear enlargement and hyperchromasia, loss of cytoplasmic mucus and mitotic figures. Both mucosa and underlying stroma are inflamed and there may be granulation tissue formation.

Cytological findings: repair and regeneration^32–36

• Immature population of parabasal, metaplastic and reserve cells

• Repair cells, fibroblasts and inflammatory cells.

Repair cells are thought to originate from both epithelial and stromal cells,³⁰ the former showing varying degrees of differentiation towards squamous and columnar epithelium. Epithelial cells tend to occur in flat syncytial sheets in which uniform polarity is maintained, often resulting in a streaming appearance. They have enlarged oval pleomorphic nuclei containing one or more eosinophilic large nucleoli (Fig. 25.11), which indicate active protein synthesis in fast growing cells, and multinucleation is often present. The chromatin pattern is usually fine and regular but may be slightly coarse and hyperchromatic. The cytoplasm is abundant and has ragged margins; there is often evidence of leucophagocytosis. Mitotic figures may be seen.

Fig. 25.11 Repair changes in metaplastic squamous cells. The cells form a flat syncytial sheet and have enlarged nuclei with prominent nucleoli and sharply defined uniform nuclear borders. Note also the intercellular ‘windows’ and associated acute inflammatory cells (PAP).

Cells thought to be fibroblasts or stromal cells tend to occur in aggregates with oval nuclei and ribbon-like extensions of poorly defined cytoplasm (Fig. 25.12). The chromatin is uniformly finely granular. Single or multiple macronucleoli are present and are occasionally irregular. Other cell types to be found include parabasal cells, metaplastic squamous cells, reserve cells which may be atypical, neutrophil polymorphs, red blood cells and cellular debris.

Fig. 25.12 (A) Repair changes in stromal cells in a cervical smear from a 78-year-old-woman. The cells are elongated, with ill-defined cytoplasm and have prominent nucleoli (PAP). (B) Granulation tissue found on biopsy of cervix of patient whose smear is illustrated in (A). The fibroblasts within the newly formed tissue are similar to the stromal cells found in the smear (H&E).

(Courtesy of Professor B. Naylor, Michigan, USA.)

Diagnostic pitfalls: repair and regeneration

Although the repair process shares some features with adenocarcinoma and large cell non-keratinising squamous carcinoma, repair cells tend to display uniformity in numbers of chromocentres and nucleoli, an even distribution of chromatin and round smooth nuclear outlines with thin nuclear membranes, and uniform polarity; these features are not seen in malignant cells. Malignant cells occur singly as well as in groups, whereas repair cells are almost invariably grouped. A tumour diathesis may accompany carcinoma cells, while repair cells are frequently associated with neutrophil polymorphs.

When the chromatin of repair cells is coarse and hyperchromatic and the macronucleoli are pleomorphic and very prominent, they are said to be atypical and are difficult to distinguish from malignant cells. While the clinical significance of atypical repair is controversial, a repeat sample for borderline nuclear abnormality (atypical squamous cells of undetermined significance), as discussed in previous chapters, may be necessary, or a biopsy if there is a clinical suspicion of malignancy.^36–39 A recent study has suggested that reflex molecular analysis for HPV performed on LBC samples is helpful in predicting the possible association with underlying CIN.⁴⁰