A9. Cervical cancer; symptoms and diagnosis

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.

Clinical features

Early cervical cancer is frequently asymptomatic. The most common symptoms are:

• Abnormal vaginal bleeding (metrorrhagia, hypermenorrhoea)
  • Especially postcoital bleeding
• Vaginal discharge
• Dyspareunia
• Pelvic pain

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.