Cervical cancer

Background information

Cervical cancer is a common malignancy of woman’s reproductive organ that develops in the cervix of the uterus. The uterus is composed of smooth muscle tissue and consists of the uterine body which is located inside the pelvis and is the location where pregnancy develops, and the cervix uteri located partially in the vagina.

The role of the cervix is to hold the developing pregnancy inside the uterus by tightly closing the cervical canal. During labour, the cervical canal opens and becomes much wider. In periods other than pregnancy, the narrow canal of the cervix forms a passage for sperm, protects against infections, helps remove menstrual blood, and contractions of the cervix to women’s feeling of orgasm.

Cervical cancer develops mainly in its outermost part, located in the vagina, referred to as ectocervix. It forms a border between two types of epithelium: glandular epithelium that lines the cavity and canal of the cervix and the squamous epithelium that covers the vaginal part of the cervix and the vagina. It is in that particular site, known as transformation zone, that CC develops. Cancer is essentially caused by genetic mutations or changes at the DNA (gene) level. The information contained in DNA determines, among others, the structure of a cell, its functions and interactions with other cells. Changes at the DNA level cause the mutated cell to stop cooperating with other, healthy cells, stop performing its functions and escape the close control of the organism. Being out of control, the mutated cells start growing exponentially to create a tumour, invade and destroy neighbouring tissue and form metastases (develop new foci of cancer away of its original site).

Cervical cancer develops due to prior human papillomavirus (HPV) infection. The neoplastic process is preceded by cervical intraepithelial neoplasia (CIN) formerly referred to as cervical dysplasia or preinvasive cancer. CIN may progress into invasive cancer; therefore, it is very important to detect those changes at an early stage by a cervical screening test.

Statistics

The CC incidence in Poland is at an average level as compared to other countries. In 2011, 3,078 new cases were diagnosed and 1,735 deaths recorded. Women below 20 years of age rarely develop that type of cancer, but the incidence grows with age. Cervical cancer occurs most often in middle-aged women (45-65 years), who account for 50% of all women affected by CC.

Clinical picture

At early stages, CC does not usually cause any noticeable symptoms. Therefore, it is so important to have regular gynaecological exams combined with cervical screening tests.

It takes from three to ten years for cervical cancer to develop from a precancerous condition. Most women with precancerous changes do not have any characteristic symptoms.

Symptoms reported by patients are of a non-specific nature:

• bloodstained discharge with unpleasant smell
• intermenstrual bleeding
• contact bleeding after intercourse
• pain in the abdomen
• pain in the lumbosacral region.

CC spreads locally by invading the surrounding tissue and organs. It invades the parametrium and the wall of the pelvis minor; direct pressure of the tumour on the ureter may lead to ureteric stricture that causes hydronephrosis, pyonephrosis, pyelonephritis and uraemia. Invasion to the rectum leads to the formation of a fistula. Cancer may also infiltrate the bladder wall and vagina, less often the body of the uterus. Cervical cancer may produce metastases to the lymph nodes, as well as lungs and bones.

Risk factors

The main risk factor of cervical cancer is human papillomavirus (HPV) infection, mainly the types 16, 18, 31, 33, 45. Other risk factors:

• Smoking
• Family history of cervical cancer
• HSV-2 vaginal infection
• Chlamydia, HIV, CMV, EBV infection; persistent bacterial vaginal infection
• Immunosuppression
• Frequent change of sexual partners or having sexual contacts with a partner who had/has many sexual partners
• Numerous pregnancies and childbirths, especially at young age
• Uncircumcised sexual partners
• Past radiotherapy to the pelvis minor
• Prostaglandin in the sperm
• Early initiation of sexual activity
• Low socioeconomic status
• Shortage of vitamin A, karotenoid and vitamin C
• Exposure to diethylstilbestrol
• Use of oral contraceptives

Diagnosis

Screening tests for CC contribute to lower morbidity and mortality. Owing to those tests, many patients are diagnosed with premalignant changes (CIN2–3) or early (preclinical) stages of CC and, if abnormalities are found in the pap test, referred for colposcopy and biopsy to collect tissue specimens.

In the case of clinical forms, a lesion within the cervix is detected during a gynaecological exam from which biopsy is taken.

The most common histological type of CC is squamous cell carcinoma (approx. 80%), followed by a much less prevalent adenocarcinoma (approx. 10%). Very rare histological types are: small-cell carcinoma, primary lymphoma and sarcoma of the cervix. When CC is confirmed histopathologically, it is necessary to determine its clinical stage and plan treatment.

To this end, the following exams need to be performed:

• full medical exam (interview and physical examination)
• gynaecological exam (per vaginam and per rectum);
• X-ray imaging of the chest
• basic blood and urine tests

At more advanced stages, in order to plan treatment, imaging procedures (CT, MRI, PET-CT) are performed and fine-needle aspiration biopsy (FNAB) of the lymph nodes and/or parametrium taken.

Course of disease

The course of an untreated disease depends on biological characteristics of cancer in a given patient. The tumour may either grow slowly or develop to a large size within a few weeks invading the surrounding organs. At an advanced stage, distant metastases may occur in other organs impairing their functions. Untreated CC leads inevitably to death.

When the tumour is detected at an early stage (screening, regular gynaecological exams!), five-year survival rate is over 90%. Early detected preinvasive changes (non-infiltrating) are 100% curable. One-year survival is approx. 85%. Unfortunately, Poland is among countries with the lowest CC 5-year survival rate in Europe (approx. 54% vs. 67% for Europe). Survival rate goes down with clinical and pathomorphological stage of malignancy.

Treatment

Treatment method depends on the cancer stage at diagnosis. If the tumour it is not large, i.e. Does not go beyond the cervix, and its diameter is smaller than 4 cm, the best outcome is achieved by surgery. At very early stages, particularly in young women who want to conserve their fertility, it is sufficient to only remove the cervix uteri alone with the pelvic lymph nodes. Thus, the patient has still a chance for natural pregnancy. The most common, however, is a radical removal of the uterus along with the pelvic lymph nodes, or generally speaking, the whole uterus with surrounding tissue and regional lymph nodes. The surgery is usually carried out by opening the abdomen (laparotomy), although laparoscopic or even transvaginal approaches can also be used.

Unfortunately, in Poland, too many cases are still diagnosed at advanced non-operable stages, therefore, radiotherapy remains the most frequently used method of CC treatment. It involves directing a beam of ionising radiation on the tumour and its surrounding tissue to destroy dividing cells, such as cancerous cells. Radiation is generated in specialised medical device, so-called accelerators, or is produced by specially prepared radioactive elements.

Radiation therapy of cervical cancer usually consists of two stages: radiation of the tumour ‘from outside’ (using an accelerator, through the skin and health tissue surrounding the tumour), and from inside by placing a radioactive element inside the tumour (in the cervical canal) which does not damage healthy tissue around the tumour. Radiation dose is limited by the so-called normal tissue tolerance as a sort of compromise between damaging the tumour and conserving normal tissue that surround it. Organs such as the bladder or rectum are sensitive to radiation and may be damaged by too high a dose. Radiotherapy is now a very complicated treatment method using state-of-the-art medical devices and computers.

Radiotherapy is used as an additional treatment after surgery, or adjuvant treatment. After the removal of the tumour, the pelvis minor, where the involves uterus is located, is irradiated to destroy singular, invisible cancer cells.

Chemotherapy – in particular cisplatin – is significant in the treatment of CC as the so-called radiochemotherapy. Is is applied in small doses as an addition to radiotherapy. It supports the activity of ionising radiation on the tumour and improves treatment outcome as compared to radiotherapy alone. Stand-alone chemotherapy, however, is of limited importance in the treatment of CC as this type of cancer is moderately sensitive to that method. It is only applied in the case of incurable disease when other methods may not be used.

Side effects

Radiotherapy of cervical cancer is well tolerated. Adverse effects may appear both during radiotherapy and many months or even years afterwards. The most common side effects are general weakness and skin changes at the irradiated site. Detailed list of side effects:

During and immediately after (up to 3 months) radiotherapy:

Frequent:

• redness of the skin at the irradiated site

• loss of hair at the irradiated site

• redness in the crotch region,

• vaginal dryness, burning sensation, vaginal discharges

• menstrual disorders,

• stomach ache,

• bloated feeling,

• nausea, vomiting (rarely),

• lack of appetite,

• pain in the rectal region,

• defecation disorders – diarrhoea, bloating, increased amount of gases, mucosa in the, pain while emptying the bowels,

• urinary disorders – feeling of bladder pressure, more frequent urination, painful urination,

• general weakness,

• fatigue,

Rare:

• blood in the stool,

• blood in the urine,

• bleeding from the vagina,

• mucosal peeling in the crotch region.

Long after radiotherapy (more than three months):

Frequent:

• reduced bladder volume – more frequent urination,

• persisting defecation disorders – more frequent defecation or bloating

• vaginal dryness, vaginal discharge

• bloodstained vaginal mucosa after sexual intercourse,

• discomfort, pain when having sexual intercourse

• no desire of sexual contacts,

• infertility,

• symptoms of menopause,

• fatigue,

• skeletal pain in the pelvis.

Rare:

• cystitis

• bladder necrosis

• persistent bladder bleeding

• rectal bleeding

• intestinal obstruction

• fistulas: intestinal, rectal/vesical, rectal/vaginal, vesical/vaginal

• discolouring of the skin at the irradiated site

• feeling of dry skin

After treatment

Follow-up visits after primary treatment should be scheduled every three months during the first two years of the follow-up period, and then every six months up to fiver years of follow-up and every year after five years. A follow-up visit must include an interview and physical examination, full gynaecological check-up and blood smear test.