A7. Premalignant disease and carcinoma in situ of the uterine cervix; diagnosis and therapy

Last updated on June 9, 2021 at 16:44

Definition and epidemiology

Cervical intraepithelial neoplasia (CIN) is a precursor to cervical carcinoma. Its clinical importance lies in its utility in preventing cervical cancer.

Cervical carcinoma is a “controllable”, highly preventable cancer for three reasons:

  • There is a precursor lesion (CIN) which progresses slowly to cancer
  • There is an inexpensive and non-invasive screening test for CIN (Pap smear)
  • The precursor lesion can be treated simply and effectively to prevent progression to cancer

Additionally, HPV vaccines (topic A8) are available which effectively prevent HPV-related cervical cancer. For these reasons, cervical cancer is a preventable disease which, according to the WHO, no person should die from.

Etiology

Cervical cancer, and by extension CIN, is highly related to infection by high-risk HPV serotypes 16, 18, 31, 33, and 45. For this reason, the risk factors for cervical cancer are related to the risk factors for HPV infection:

  • Multiple sex partners
  • Early sexual debut
  • Early childbearing
  • Multiparity

There are also some risk factors which are unrelated to HPV infection:

  • Cigarette smoking
  • In-utero exposure to DES
  • Low socioeconomic status
  • Immunosuppression

Pathology

Cervical cancer originates from the squamocolumnar junction of the cervix, where the squamous epithelium of the ectocervix meets the columnar epithelium of the endocervix. The location of the squamocolumnar junction depends on age and parity, so that a young, nulliparous woman has it around the external os, while an older, multiparous women have it more internally.

For diagnosis with a punch biopsy, conisation or other histological sample, we use the WHO classification. This is a histological classification, to be used with histological samples:

  • CIN I – mild dysplasia
    • Corresponds to LSIL
  • CIN II – moderate dysplasia
    • Corresponds to HSIL
  • CIN III – severe dysplasia (carcinoma in situ)
    • Corresponds to HSIL
  • Invasive cancer

Pap smear

The Pap smear is the investigation used for screening for CIN and cervical cancer. It’s named after Greek physician George Papanicolaou. It is performed with the patient in the lithotomy position. A speculum is used to open the posterior and anterior vaginal wall to visualise the cervix. A brush is used to collect cells from the cervix and the posterior vaginal fornix. This cytologic specimen is then examined by a cytopathologist, who will examine and describe the squamous cells and the glandular cells of the specimen.

For screening purposes with Pap smear, CIN is classified according to the Bethesda 2001 system. This is a cytological classification, to be used for cytological samples. According to this system, the cells can either be:

  • Squamous cells of the sample
    • Negative for intraepithelial lesion or malignancy (NILM)
    • Atypical squamous cells (ASC)
      • ASC of undetermined significance (ASC-US)
      • ASC but HSIL cannot be excluded (ASC-H)
    • Low-grade squamous intraepithelial lesion (LSIL)
    • High-grade squamous intraepithelial lesion (HSIL)
    • Squamous cell carcinoma
  • Glandular cells of the sample
    • Atypical cells, non otherwise specified (NOS)
    • Atypical cells, favour neoplastic
    • Endocervical adenocarcinoma in situ (AIS)
    • Adenocarcinoma

In Hungary, screening with Pap smear is recommended once a year in sexually active women of all ages. If older than 65, screening is recommended every two years.

PCR tests for HPV can also be performed on cervical cytological samples.

Colposcopy

Colposcopy uses a special equipment called the colposcope to magnify and visualise the cervix directly. It can be used to guide sampling for the Pap smear or punch biopsy. It is used after Pap smear, in cases of ASC-US, ASC-H, LSIL, and HSIL.

By applying dilute acetic acid to the surface, we can differentiate between atypical and normal cells. Atypical cells will be more whitish.

We can also apply 2% iodine to the surface, which is called Schiller’s test. Healthy cells pick up the iodine and change colour to mahogany brown, while atypical cells will remain white or yellowish.

With colposcopy we can also see other features which are suspicious of malignancy, like exophytic lesions and hypervascularisation.

Treatment

Treatment of premalignant lesions is conisation, the excision of a triangular part of cervical tissue containing the lesion + a safety margin. This may be performed with a scalpel, an electrical knife, or with a laser.

In premenopausal women, the squamocolumnar junction lies externally. It is this junction which is essential to remove, so a flatter cone can be cut out. In postmenopausal women, the junction lies more internally, and so a deeper cone must be cut out to ensure that the junction is cut out.

Conisation must always be followed by fractional curettage. This involves obtaining cytological specimens by abrasion of the remnants of the cervix, after which the cervix is dilated, and samples are obtained from the uterine cavity as well. These specimens are then examined by a cytopathologist.


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