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

Cervical cancer is the cancer of the uterine cervix. It's the 4th most common cancer in females, but the 6th most common cause of cancer death. It mostly affects women 35 - 50 years old. It progresses from cervical intraepithelial neoplasia (CIN), which is the precancerous lesion of cervical cancer. Human papilloma virus (HPV) infection is the cause in virtually all cases.

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

• The precursor lesion (CIN) 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 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. Deaths from cervical cancer mainly occurs in countries without access to screening and vaccines. The 5-year survival is approximately 60%.

Etiology

Cervical cancer, and by extension CIN, requires infection by high-risk HPV serotypes (16, 18, 31, 33, +++). HPV 16 is the most carcinogenic and accounts for 50%+ of cases. 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

Pathology

Cervical cancer originates in the squamocolumnar junction of the cervix as cervical intraepithelial neoplasia, and takes years or even decades to develop into invasive cancer. The squamocolumnar junction of the cervix is 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 young, nulliparous women has it around the external os, while older, multiparous women have it more internally.

There are two major types of cervical carcinoma, squamous carcinoma and adenocarcinoma. Squamous cell carcinoma accounts for 80-90% of cases, while adenocarcinoma accounts for the remaining cases. Other types, including neuroendocrine type, are very rare. Adenocarcinoma has a worse prognosis.

Cervical intraepithelial neoplasia

CIN is the precancerous lesion of cervical cancer. According to severity, CIN is classified as CIN 1 to CIN 3, where CIN3 has the highest risk of malignancy. A significant number (possibly up to 70%) of CIN 2+ lesions regress over time rather than progress to cancer, and this number is even higher for CIN 1 lesions. 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.

CIN 1 - 3 are histological diagnoses, which must be obtained by punch biopsy, conisation or other histological sample. CIN 1 is characterised by mild dysplasia and changes present in the lower third of the basal epithelium. CIN 2 is characterised by moderate dysplasia and changes present in the lower two thirds of the basal epithelium. CIN 3 is characterised by severe atypia or squamous carcinoma in situ and changes present in more than two thirds of the basal epithelium. By definition, the basal membrane is intact in CIN. If it is not, the diagnosis is invasive cervical cancer. We use the term “CIN 2+” to refer to any of CIN II, CIN III, or invasive cancer.

When examined with a Pap smear, usually for screening purposes, 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

Diagnosis and evaluation

Cervical examination may reveal ulceration, induration, or an exophytic tumor. Biopsy is required for diagnosis. Cervical cytology (Pap smear) should always be performed in case of symptoms, and involves scraping of ectocervix and endocervix with spatula or brush. Cervical cytology has a high specificity but moderate sensitivity.

If physical examination shows a suspicious lesion, a punch biopsy should be taken directly from it. If no tumour is visible, colposcopy with acetic acid or Schiller test (applying iodine solution) should be used to look for suspicious areas to biopsy.

If no suspicious lesions are found or biopsy is negative but malignancy is still suspected, cervical conization can be performed and examined histologically.

If cancer is suspected, we should look for involvement of the parametrium by rectovaginal examination. Further evaluation of the parametrium can be accomplished with PET/CT or MRI.

Cervical cytology

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.

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 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.

Management

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

Prevention

Regular screening with cervical cytology (Pap smear) is recommended for females in sexually active ages. HPV vaccination before sexual debut also decreases the risk.

In Norway, this includes women at the age of 25 - 69, and involves screening every 5 years. The cytology specimen is first analysed for HPV. If there is no HPV, the cytology specimen is not examined. If there is HPV, the specimen is examined for CIN. If there are signs of CIN or HPV positivity, more frequent screenings or colposcopy and biopsy are recommended, depending on the type of CIN and HPV.

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.