Benign mimics of cervical cancers

A vast number of benign lesions in the cervix are encountered in day to day practice. Many of these can mimic in situ and invasive neoplastic lesions and many precursor lesions and malignant neoplasms may mimic benign conditions. This article will describe a large number of common benign lesions and where appropriate, will discuss what these mimic. The majority of the lesions are glandular in type(1,2). The benign lesions can be placed into five main groups of conditions. The first group does not actually include lesions but instead comprises physiological conditions. There are some lesions that cannot be readily assigned to any of these groups. The five groups are:


Immature squamous metaplasia (ISM)
This occurs within proliferation of reserve cells. There is inconspicuous intracytoplasmic glycogen. ISM is often sharply demarcated from mature squamous epithelium by a perpendicular line and can mimic high grade CIN. There is cell organisation and cohesion and no atypia (Fig.2).
Mitoses are infrequent. p16 is only patchily positive. Immature squamous metaplasia can also mimic a stratified mucinous intraepithelial lesion (SMILE) but in the latter, mucin is present throughout the full thickness of the lesion, whereas in immature squamous metaplasia, if there is any mucin present, it is usually confined to the superficial portion of the epithelium (Fig. 3).

Tubal metaplasia (TM) (5)
This renders epithelium similar to fallopian tube lining. There are more ciliated cells than normal together with secretory and reserve cells or intercalated cells (Fig. 4)  CGIN is p16 and mib-1 positive and generally bcl-2 negative.

Endometriosis (7)
This comprises ectopic endometrial glands and stroma anywhere in the cervix but usually in the superficial one third of the wall (Fig.5). It can be cystic or may even form a circumscribed mass when in the form of an endometrioma.
During pregnancy or with progesterone therapy, decidual change in the stroma may be noted.
The pathogenesis of cervical endometriosis is either by implantation at surgery or trauma or true metaplasia like tubal and tubo-endometrioid metaplasia. It can mimic CGIN although the presence of stroma together with haemorrhage in endometriosis helps to distinguish it from the neoplastic process.

Atypical oxyphilic metaplasia
This is similar to eosinophilic metaplasia in the endometrium. It generally does not cause any problems with regard to mimics of neoplasia.

Epidermal metaplasias
This includes the presence of epidermis, sebaceous glands and hair follicles within the cervix. It may be a form of mesodermal metaplasia or true heterotopia.

Ectopic prostatic tissue
These are considered to derive from paraurethral Skene's glands and the ectopic tissue is usually on the ectocervix. It comprises of a glandular component encircling squamous elements. They are usually PSA and PAP positive. They do not generally mimic any neoplasia.

Glandular hyperplasias
Microglandular hyperplasia (MGH) (8,9) This is a benign proliferation of endocervical glands and is often an incidental
The lesion is usually confined to the inner half of the cervical wall. It tends to maintain a lobular architecture and mitoses can be seen. It is generally CEA negative. It can mimic MDA.

Diffuse laminar endocervical glandular hyperplasia (DLEGH) (12)
This is a rare lesion which comprises tightly packed, small to medium-sized glands present usually in the upper one third of the wall. No lobulation is seen but instead there is a sharp demarcation by a straight line between the hyperplastic glands and the underlying stroma immunohistochemistry usually aids distinction from these neoplastic entities (14) .

Reserve cell hyperplasia
This is seen in the transformation zone and is common in areas of microglandular hyperplasia. It mimics CGIN or SMILE. It is generally is ER, PR cyclin-D1, bcl-2 and CD44 positive.

Reactive changes to inflammation
These are often seen in the form of disorganised cells with nuclear atypia. The nuclei are generally uniform and there is no mitotic activity (Fig. 9). They contain prominent nucleoli. The reactive changes affect both squamous and glandular epithelium and are often seen in ectropions. They mimic high grade or low grade CIN and also high grade CGIN.

Radiation atypia (15)
This affects both squamous and glandular epithelium and comprises nuclear enlargement with ground-glass appearance and nuclear and cytoplasmic vacuolation. There may be multinucleation and most nuclei contain multiple nucleoli (Fig.10).

Lymphoid follicles
The presence of lymphoid follicles is often associated with chlamydial infection.
They do not mimic any particular neoplasia.
However, any high-grade CIN present above any lymphoid follicles can be spongiotic or thin and easily overlooked (Fig. 11).

Decidual change
Can be polypoidal and mimic malignancy. or CGIN (no vacuolation is seen in this).

Papillary endocervicitis
This is commonly seen in chronic inflammation. This comprises papillae of various sizes which are filled with inflammatory cells. This is not really a mimic unless florid when the main differential diagnosis to consider is a villoglandular adenocarcinoma.

Pseudo-invasion of benign squamous epithelium following cervical biopsy
This comprises entrapped benign squamous epithelium following loop excision or punch biopsy. It includes hypereosinophilic cells with a giant cell reaction and granulation

tissue-like and inflammatory stromal response
and it mimics squamous cell carcinoma.

Diathermy changes
Severe nuclear damage can be seen as a result of diathermy. This renders enlargement and hyperchromasia-like effect and can mimic high grade CGIN, particularly when it affects glandular epithelium.

Post-operative spindle cell nodule
This is similar to that seen in the vulva or

Endocervical polyps
These occur mainly in the 4th to 6th decades and are generally up to 2 cm in size.

They can be vascular, fibrous or heavily inflamed
and there is often microglandular hyperplasia.
Within these polyps, there can be CIN or CGIN.

Mesodermal stromal polyps
These occur in pregnancy and are

Papillary adenofibroma
This is a rare lesion comprising endocervical or tubal glands surrounded by stroma which is fibrous and forming broad papillary projections or outlines (Fig.12). They can mimic villoglandular adenocarcinoma but more importantly an adenosarcoma and particular attention needs to be paid to the stromal component.

Squamous papilloma
These are similar to fibroepithelial stromal polyps and do not show any HPV association.                       6. Tubal and tubo-endometrioid metaplasia of the uterine cervix: unemphasised features that may cause problems in differential diagnosis. A report