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

Page created on June 6, 2021. Last updated on January 17, 2022 at 13:24

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.


Cervical cancer, and by extension CIN, requires infection by high-risk HPV serotypes (16, 18, 31, 33, +++). 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 (although infection is still required):

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


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

We use the term “CIN II+” or “CIN 2+” to refer to any of CIN II, CIN III, or 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, to diagnose HPV infaction and determine the serotype.


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 indicated if the Pap smear showed ASC-US, ASC-H, LSIL, or HSIL.

By applying dilute acetic acid to the surface, we can differentiate between atypical and normal cells, which gives an indication of where to take the sample/biopsy. Atypical cells will be stained white.

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

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


A significant number (possibly up to 70%) of CIN II+ lesions regress over time rather than progress to cancer. However, as of yet we have no way of distinguishing lesions which will progress from those who will regress. As such, all CIN II+ lesions must be treated.

Treatment of CIN II+ 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 is often followed by dilation and 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 samples are then examined by a cytopathologist.

CIN I is not an indication for treatment, but rather for regular follow-up until it progresses or regresses.

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