Diseases of the Cervix

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The cervix is an important site of pathology, particularly in women of reproductive age. The ectocervix is covered by squamous epithelium, and the endocervical canal by mucus-secreting columnar epithelium, which shows glandular downgrowths. At various stages in a woman's reproductive life, the junction between the squamous and columnar epithelium migrates onto the convexity of the ectocervix, then back into the endocervical canal. This squamocolumnar junction is the seat of most of the epithelial diseases that occur in the cervix. 

The original squamocolumnar junction is usually located in the region of the external os, but its precise location at birth is influenced by exposure to maternal hormones in utero.
Around puberty, hormonal influences cause extension of the columnar epithelium onto the ectocervix, forming an ectropion or cervical erosion. This process is augmented by a first pregnancy, particularly when it occurs shortly after menarche.

Before puberty, the pH of the vagina and cervix is alkaline, but afterwards bacterial breakdown of glycogen in the vaginal and cervical squamous epithelium renders it an acidic environment, the pH being about 3.

Exposure of the sensitive columnar epithelium of the ectropion to the post-pubertal acidic environment of the vagina induces squamous metaplasia and a transformation zone between the endocervical columnar epithelium and the ectocervical squamous epithelium. This zone is composed of new squamous epithelium in an area previously occupied by columnar epithelium.
Thus the squamocolumnar junction is of variable size, but its site always approximates to the external os. In older women it may retreat into the endocervical canal.

The mobility of the squamocolumnar junction, the development of ectropion, and the formation of the transformation zone are:
(a) The squamocolumnar junction is originally situated in the region of the external os.
(b) At puberty the endocervical epithelium extends distally into the acid environment of the vagina, forming an ectropion.
(c) A transformation zone forms as squamous epithelium re-grows over the ectropion. The openings of the crypts may be obliterated in the process, which leads to the formation of mucus-filled Nabothian follicles.

Chronic cervicitis is produced by the same organisms responsible for infective vaginitis. The term 'chronic cervicitis' is sometimes applied inaccurately by clinicians when the area of ectocervix around the external os is red and irregular; in most cases this is not inflammation, but represents the extension of columnar epithelium onto the external os, sometimes called ectropion or, inaccurately, a 'cervical erosion'.

Genuine chronic endocervicitis, with a heavy lymphocytic and plasma cell infiltrate, may be found in association with infections of the vagina by Trichomonas, Candida, Gardnerella and the gonococcus.

Cervical polyps are a common cause of intermenstrual bleeding. 
Cervical polyps are common abnormalities which, through erosion and ulceration, may cause intermenstrual bleeding. They are seen in about 5% of women. Macroscopically they appear smooth, rounded or pear-shaped, and are typically 
1-2 cm in diameter. The polyps derive from the endocervix, protruding from the cervix through the external os. They are composed of endocervical stroma and glands, the latter often being distended with mucus. The surface of the polyp may show ulceration and inflammation and, if long-standing, there may be surface squamous metaplasia.

Benign tumours of the cervix are uncommon, the most frequent being leiomyomas

True benign neoplasms of the cervix are uncommon, most nodules associated with the cervix being endocervical polyps. Leiomyomas may occur in the cervix, but are less common at this site than in the uterus.

HPV infection is common in the ectocervical epithelium and is an important aetiological agent in cervical cancer

HPV infection of the cervix is sexually acquired. Over 70 sub-types of HPV have been defined, each of which has been allocated a number. 

Occasionally, HPV infection may produce papillary lesions of cervical squamous epithelium (condyloma acuminatum), which are similar to those seen on the vulva . They are usually located on the ectocervical squamous epithelium or on the squamous epithelium of the transformation zone, and may be multiple.

More often, HPV infection causes flat condylomas.} These cannot normally be seen with the naked eye, but may be recognizable on colposcopic examination after painting the cervix with dilute acetic acid, which turns them white. Histologically the epithelium in flat condylomas is abnormal, with binucleate cells (particularly in the upper layers of the epithelium), and so-called 'koilocytic change' in the most abnormal epithelial cells. These viral changes can be recognized on cervical-smear cytology. Both patterns of wart-virus involvement of the cervical squamous epithelium are most frequent in the transformation zone epithelium, and may co-exist with changes of intraepithelial neoplasia.

Cervical intraepithelial neoplasia is an important precursor of invasive malignancy

The metaplastic epithelium of the transformation zone is susceptible to change during reproductive life. Mild degrees of nuclear enlargement can be seen in response to chronic inflammation, in reparative epithelium, and in association with HPV infection. However, more severe atypia is now regarded as a pre-neoplastic proliferation and is called cervical intraepithelial neoplasia (CIN). This change takes place in the metaplastic epithelium of the transformation zone of the cervix and is usually associated with infection by HPV.

Three grades of severity are recognized, dependent upon what proportion of the thickness of the cervical epithelium is replaced by atypical cells.

CIN I corresponds to mild dysplasia. Atypical cells are confined to the lower third of the epithelium, the upper two-thirds showing normal differentiation and maturation with flattening of cells.

CIN II corresponds to moderate dysplasia. Atypical cells occupy the lower half of the epithelium, but evidence of differentiation and maturation with flattening of cells is seen in the upper half. Nuclear abnormalities may extend through the full thickness of the epithelium, but are most marked in the lower half, where there may be increased mitoses with some abnormal forms.

CIN III corresponds to severe dysplasia and carcinoma in situ. Atypical cells extend throughout the full thickness of the epithelium, with minimal differentiation and maturation on the surface. Mitotic figures and abnormal mitoses are present through all layers, and there may be extension of the change along endocervical crypt necks, and foci of true microinvasion.

These abnormal epithelial changes occur in the transformation zone, but may extend over the ectocervical surface and up the endocervical canal. In about 10% of cases, atypia termed cervical glandular intraepithelial neoplasia (CGIN) is also seen in endocervical epithelium.

Diagnostic cervical cytology

The development of abnormalities in the cervical epithelium is an important factor in the prevention of subsequent invasive carcinoma of the cervix. Detection of abnormal cells is based on the presence of abnormal cytology. Using a specially shaped spatula, cells are scraped from the ectocervix and lower cervical canal and smeared onto a slide. They are fixed in a preservative solution and sent to a pathology laboratory for cytological examination after the addition of Papanicolaou stain (the origin of the term 'Pap smear'). In CIN, the exfoliated cells have an increased nuclear:cytoplasmic ratio and a clumped, irregular chromatin pattern, being termed dyskaryotic.
If atypical epithelial cells are detected in a cervical smear, patients are recalled. The site of abnormal epithelium is identified by colposcopy, and the diagnosis confirmed by biopsy of the abnormal area. If the lesion is non-invasive and completely visible, not extending high up into the endocervical canal, ablation of the atypical area can be performed using laser or cryotherapy. If the topmost edge of the lesion cannot be seen in the endocervical canal, the lesion has to be removed as part of an excision biopsy.

Invasive carcinoma of the cervix is most commonly squamous-cell carcinoma

Invasive carcinoma of the cervix may occur at any time during the reproductive and post-menopausal years, but the average age of development is about 50 years. It accounts for 3-5% of cases of carcinoma in females.

Macroscopically, early lesions appear as areas of granular irregularity of the cervical epithelium, progressive invasion of the stroma causing abnormal hardness of the cervix. Late lesions appear as fungating, ulcerated areas, which destroy the cervix.

The vast majority of carcinomas of the cervix are squamous cell carcinomas, arising from the transformation zone or ectocervix. Lesions fall into three histological patterns: keratinizing squamous cell carcinoma, non-keratinizing large-cell squamous carcinoma, and non-keratinizing small-cell squamous carcinoma.

Prognosis of squamous cell carcinoma of the cervix is related to stage at diagnosis

The common presenting symptom is vaginal bleeding in the early stages, but advanced neglected tumours may cause urinary obstruction due to bladder involvement.

The histological type of the tumour is less important for prognosis than is the staging at diagnosis. Microinvasive carcinomas show minute foci of very superficial invasion, only detected histologically, and have a very good prognosis after local excision. Invasive carcinomas are staged according to the degree of local invasion, and survival is related to stage. Invasion of paracervical and external iliac nodes occurs early.
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