55. Inflammations, tumourlike lesions and tumours of the cervix. Carcinoma of the cervix (pathogenesis, pathomorphology, screening)

Page created on April 23, 2019. Last updated on April 28, 2020 at 16:09

Introduction

The cervix is the “neck” of the uterus, hence the name. It’s divided into the exocervix and the endocervix. The exocervix is covered by stratified squamous epithelium while the endocervix is covered by simple columnar epithelium. The junction between the two is called the squamocolumnar junction.

Cervicitis

Cervicitis can be infectious and non-infectious. It’s most frequently caused by common sexually transmitted infections. Here are the most important causes:

• Infectious
  • Chlamydia trachomatis (40% of cervicitis cases in STD clinics)
  • Neisseria gonorrhoeae
  • HSV-2
  • Trichomonas vaginalis
• Non-infectious
  • Local trauma
  • Chemical irritation

It most frequently presents with vaginal discharge and pain during sex. The infection may spread to the upper genital tract, causing pelvic inflammatory disease.

Cervical cancer

Virtually all cases of cervical cancer are caused by HPV. The virus infects the lower genital tract, especially the cervix at the squamocolumnar junction. Most HPV infections of the cervix are cleared by the immune system, but some of those infections that aren’t cleared will progress to cervical intraepithelial neoplasia (CIN).

Because of the close relationship between HPV infection and cervical cancer, their risk factors are the same. Of course, none of these risk factors actually predispose you to cervical cancer if you don’t also acquire HPV infection:

• Early onset of sexual activity
• Multiple sexual partners
• Immunosuppression
• Smoking

The HPV subtypes that are associated with cervical cancer are those who are high-risk: 16, 18, 31 and 33. High-risk HPV subtypes integrate their genome into the host cell genome and start expressing proteins coded in their genome. Recall from microbial carcinogenesis that these HPV subtypes produce two potent oncoproteins called E6 and E7, which inhibit p53 and pRb respectively. This promotes growth and increases the susceptibility to additional mutations that may eventually lead to CIN and later invasive cancer.

While HPV is necessary for the development of CIN the virus cannot progress the CIN into invasive cancer. This progression is attributed to factors such as smoking, immune status and hormonal status. Mutations in genes like LKB are necessary for this progression.

CIN starts as low-grade dysplasia (CIN I) before it progresses into high-grade dysplasia (CIN II and later III). The major histological sign of HPV infection in any tissue is koilocytic change, which refers to the presence of koilocytes. These cells are squamous epithelial cells that have been infected by HPV. Koilocytes have irregular nucleus and a clear area around the nucleus, called a perinuclear halo.

CIN I is characterised by dysplastic changes in the lower 1/3 of the squamous epithelium of the exocervix. For CIN II the number is 2/3 and in CIN III all layers are dysplastic.

Only 10% of CIN II and III progress into invasive carcinoma within 10 years, as seen in the table below:

Lesion	Regress	Persist	Progress
Low grade CIN (CIN I)	60%	30%	10% to high grade CIN
High grade CIN (CIN II, III)	30%	60%	10% to carcinoma within 10 years

Squamous cell carcinoma accounts for 75% of cases of cervical carcinoma. Adenocarcinomas and mixed adenosquamous carcinomas account for 20% while less than 5% are neuroendocrine.

The Pap smear (named after the Greek doctor Georgios Papanikolaou) can detect the presence of atypical cells and koilocytes. A spatula is used to scrape epithelial cells from the ectocervix and endocervix, which are then stained and examined histologically. The Pap smear is used to screen women between the age of around 20 to around 60 for potentially premalignant lesions. The test should be performed every 3 – 5 years. The Pap smear has high specificity but low sensitivity, so the test should be repeated every few years. If the Pap smear yields positive results, HPV testing, colposcopy and biopsy may be performed. The Pap smear is more effective at detecting squamous cell carcinoma than adenocarcinoma.

Women with biopsy-documented low grade CIN are regularly observed while biopsy-documented high grade CIN are treated with surgical excision, called cone biopsy or conization. During this procedure a cone-shaped piece of tissue around the precancerous lesion is excised.

The HPV vaccine, which protects against HPV subtypes 16 and 18 are very effective in protecting against genital warts and cervical cancer. In some countries a quadrivalent variant is used, which protects against subtypes 6 and 11 as well and therefore also protects against genital warts. This vaccine has been offered to young females for long and has recently been offered to young males as well. It protects against all HPV-induced cancers, including cancer in the cervix, vulva, vagina, penis, rectum and in the upper respiratory tract.

While the vaccine is very effective it doesn’t give 100% protection, partly because 16 and 18 are not the only high-risk HPV viruses. It also doesn’t significantly protect those that are already infected. For this reason, taking the vaccine does not remove the need for routine screening.

Invasive cervical cancer most frequently develops in women who have never har a Pap smear or who have not been screened for many years. Patients present with:

• Unexpected vaginal bleeding
• White vaginal discharge
• Painful sexual activity
• Dysuria

Treatment is usually by hysterectomy and lymph node dissection; if the cancer is very small and barely invades it can be treated with cone biopsy.

A common cause of death is renal failure due to obstruction of the urinary bladder or ureters.