Section A
by Dr. S. Trompoukis, Gynecologist

Introduction

Cervical cancer is the second most common malignancy in women worldwide, after breast cancer. It is the leading cause of death from malignancies in women in developing countries, due to the lack of organized national screening programs. The peak incidence is between 45 and 55 years. Studies have shown an increase in the number of young women developing the disease (20-35 years) and the prognosis in this age group is much worse.

 

Epidemiology and Etiology

The frequency of cervical cancer varies between developing and developed countries, due to the well established screening programs with Papanicolaou (Pap) tests and the use of HPV vaccines. It may be the second most common malignancy in the developing countries, but only the tenth most common in developed countries.

 

Etiology
  • HPV: In almost all cases (99%), cervical cancer is caused by the human papillomavirus (HPV). This is a sexually transmitted virus, which is very common, as almost 50% of all women will be infected with a HPV type at some point of their lives. Most women with HPV infection will not develop cervical cancer. There are over 115 different types of HPV and most of them are harmless, do not cause any symptoms, and will pass without any treatment. About 15 HPV types are considered high risk for cervical cancer, with HPV-16 and HPV-18 being the most ongogenic, accounting for approximately 70% of cervical cancer cases. High risk HPV types are containing genetic material, which disrupt the normal cell growth, leading to a mutation, a dysplasia and eventually a tumor.

Other predisposing factors, affecting women’s chance of developing cervical cancer include:

  • Childbearing. Greater risk for women who start early or have more children. Rare in virgins.
  • Early age of first intercourse
  • Multiple sexual partners
  • Immunosuppression (in HIV patients etc)
  • Using contraceptive pill for more than 5 years
  • Smoking

There is also an association with lower socioeconomic status and poor hygiene.

 

Cervical intraepithelial neoplasia (CIN)

Invasive cervical cancer usually takes many years to develop. Before that, there is an interval of epithelial dysplasia, known as cervical intraepithelial neoplasia (CIN). There is a fairly predictable progress through the stages and the progression is very slow, taking up to 10 years. CIN1 is confined to the basal 1/3 of the epithelium and usually regress to normal in about 12-18 months. Involvement of the whole epithelium (full thickness) is known as CIN3 or carcinoma in situ. CIN is a pre-cancerous condition. Untreated CIN cases may slowly progress to invasive cancer at a rate from 12-22%. However, if the changes in the cervix are discovered early, the treatment is highly successful.

 

Symptoms

Cervical cancer may not cause any symptoms until progressed to an advanced stage. In most cases, cervical cancer causes abnormal vaginal bleeding, usually following sexual intercourse (postcoital symptom), or bloodstained discharge. In postmenopausal women, any bleeding will be unusual. In younger women, irregular bleeding may consist of heavier than normal periods, or any bleeding between her periods. Abnormal bleeding is a very common symptom and does not mean that the woman has cervical cancer. However, it is a symptom that needs to be investigated.

Pain is a sign of advanced disease. In more advanced stages, as the tumor enlarges, it can cause pelvic pain, back pain, tiredness, loss of appetite, weight loss, difficulty in urination, constipation or leg swelling.

 

Diagnosis

Changes at the cells of the cervix can be detected at an early stage, before even producing any suspicious symptoms. Most developed countries have organized national screening programs, which help to diagnose cervical dysplasia and preinvasive lesions. The evolution to invasive cancer can take up to 10 years; therefore, follow-up of these changes is very important. The three procedures of obtaining and diagnosing abnormalities are:

  • Papanicolaou (Pap) test:  Few cells are obtained from the cervix and the upper vagina, to be checked for abnormalities. Abnormal results do not imply the presence of cervical cancer, and may indicate benign inflammation, HPV inflammation, atypical squamous cells of undetermined significance (ASCUS), cervical intraepithelial neoplasia (CIN) etc. The incidence of positive Pap tests for invasive carcinoma is 4-5%. The usual recommendation is for annual screening. Any woman with abnormal Pap test should be referred for further testing.
  • Colposcopy:  A gynecologist examines the vagina and cervix via microscope. Application of 3% acetic acid and finally Lugol iodine assists in highlighting any abnormal changes. Indication for colposcopy include postcoital bleeding, positive HPV test, ASCUS and persistent CIN. A biopsy may be obtained to be checked for cancerous cells.
  • Cone biopsy:  This is minor operation that should be performed by trained personnel. It is carried out usually under local anesthesia. A small cone section is taken to be examined for abnormalities, in order to rule out the case of invasive cancer. Cone biopsy can also be used as treatment, if the abnormal cells are extending out of the range of the colposcope, in the cervical canal.

If the above suggest that a woman has cervical cancer, further tests will be needed, in order to assess the extent of the disease and decide the treatment planning. Every woman with cervical cancer will ideally obtain a referral to a gynecologic oncologist before she starts any treatment or has any surgery.

Cervical cancer can spread by direct extension to the surrounding organs (the body of the uterus, the upper vagina, the parametrium, the bladder or the rectum). Cancer can also be spread by the lymphatic system or the blood stream. In those cases, metastases can be found in such organs as liver, lungs, bones or brain.

In order to find the extension of the disease, further tests may include:

  • Pelvic examination, sometimes under general anesthetic
  • Chest X-ray, in order to see whether cancer has spread to the lungs
  • CT scan or MRI scan, to look for signs of the disease in the chest, abdomen and pelvis.
  • Positron emission scan (PET) is used as a method of imaging lymph node disease and other metastasis. However it can also be used to check patients’ response to the given treatment.

 

Staging

Staging helps oncologists to decide the best treatment options. Cervical cancer has four (4) stages (stage 0 is precancerous):

  • Stage 0:  Carcinoma in situ. Intraepithelial carcinoma.
  • Stage 1:  Carcinoma confined to the cervix.
  • Stage 1A:  microinvasive disease, depth of invasion <3mm
  • Stage 1B:  all other cases
  • Stage 2:  Carcinoma extends beyond the cervix, but not extended to the pelvic wall. Involves the vagina, but not the lower third.
  • Stage 3:  Carcinoma has spread into the lower third of the vagina and/or into the pelvic wall. Case of hydronephrosis.
  • Stage 4: Carcinoma has extended beyond the true pelvis; clinical involvement of the bladder or bowel. Spread to distant organs.

This is a simplified guide. Each stage is divided into further categories.

 

Treatment overview

The choice of treatment depends on the type of the lesion and the extension of the disease. Abnormal cells or CIN may be treated by diathermy, cryotherapy, Laser therapy or Loop excision of the transformation zone (LETZ).

In case of microinvasive disease, the treatment is controversial, but most gynecologists would suggest a cone biopsy. Depending on the age, even if there is no risk of lymphatic invasion, a simple hysterectomy may be suggested.

  • Surgery:  It is suitable for early stage cases (stage1 and some stage2). Surgery consists of radical hysterectomy and pelvic lymphadenectomy. It involves removing of the uterus, parametrium, upper third of the vagina and pelvic lymph nodes. Ovaries may be preserved in selected cases of younger women. Hysterectomy may be followed by radiotherapy, in order to prevent return of cancer.
    • In case of local recurrence, but only if the disease has not spread beyond the pelvis, a pelvic exenteration may be recommended. This major operation involves removing also the bladder, rectum and vagina.
  • Radiotherapy:  It can be used in some cases, alone or in combination with surgery or chemotherapy, usually in more advanced stages. There are two ways of radiation delivery: external and intracavitary. If radiotherapy is to be used after surgery, it should be administered immediately post operation, as prognosis is much worse if delayed. Radiotherapy can also be used in advanced stages, in order to relieve from local symptoms, such as bleeding or pain.
  • Chemotherapy:  it is usually given post-operatively, to destroy any cancer cells that have remained. It is administered alone or in combination with radiotherapy, in more advanced stages, to slow the progress and relieve from symptoms.

Whatever the choice of treatment, a very close follow-up will be recommended, at least for the first 2-3 years. The size of the tumor, the parametrial involvement and especially the presence of malignancy in the lymph nodes, are the prognostic factors.

 

Prognosis

The prognosis depends on the stage. The 5 year survival rates are generally estimated as follows:

  • Stage 1: >90%
  • Stage 2: 60-80%
  • Stage 3: 50%
  • Stage 4: <30%

Many other factors may affect patient’s prognosis, such as her general health and the degree of the response to treatment.

 

Screening and Prevention

The screening test for cervical cancer is the same routinely used to diagnose it. All sexually active women, or every woman after the age of 21 (in most countries), should be included for cervical screen with a “Papanicolaou test” annually, in order to identify any changes at an early stage. If any abnormality is detected, further testing will be recommended.

The use of condoms, and giving up smoking should be encouraged, to reduce the risk.

The last few years, an immunization vaccine is offered, against the infection of the two most oncogenic HPV types (16 &18). It is given in three doses over a six month period. The vaccination is recommended for all women aged 9-26 years. The incidence of persistent HPV infection and invasive cervical cancer, in the developed countries that have been using this vaccine, was reduced by almost 90%. However, it does not guarantee that a woman will not develop cervical cancer, and the participation at the annual cervical screening test is important and advisable.

 

Section B
by Dr. M. Tsiatas, Medical Oncologist

Treatment of cervical cancer by stage

The basis for treatment choice of cervical cancer is its stage, although other factors may affect this decision. These include the exact anatomic site of the cancer within the cervix, the histology of cancer (squamous cell or other types), the patient’s age and general condition, and the desire for pregnancy. The available therapeutic options for each stage are presented below.

Stage 1A1:

  • For the patient who desires pregnancy, the cancer is removed with a cone biopsy.
  • For the patient who does not desire pregnancy, the uterus will be removed (hysterectomy).
  • If the cancer has invaded the blood vessels or lymph vessels, a radical hysterectomy will be necessary, along with removal of the pelvic lymph nodes. Further treatment will be decided based on the histological findings of the lymph nodes.

Stage 1A2:

  • Radical hysterectomy and removal of lymph nodes in the pelvis is necessary.
  • Brachytherapy with or without external beam radiation therapy to the pelvis.
  • For patients who desire pregnancy, trachelectomy (surgical removal of the uterine cervix) and removal of pelvic lymph nodes can be performed. If the tumor has spread to the tissues next to the uterus (parametria) or to lymph nodes, then radiation therapy is usually recommended along with chemotherapy. Similar treatment is followed in case of positive margins (cancer cells at the site of surgical incision in the uterus).

Stage 1B1:

  • The best treatment is a radical hysterectomy and removal of pelvic as well as para-aortic lymph nodes. Following surgery, a combination of radiation and chemotherapy is given in case of positive margins or histologically positive lymph nodes.
  • An alternative treatment option is brachytherapy and external beam radiation.
  • For patients who desire pregnancy, trachelectomy with removal of pelvic and para-aortic lymph nodes can be discussed.

Stage 1B2:

  • The best treatment is the combination of chemotherapy with radiation therapy to the pelvis plus brachytherapy. This is usually followed by hysterectomy.
  • Alternatively, radical hysterectomy with removal of pelvic and para-aortic lymph nodes is an option. In case of positive margins or histologically positive lymph nodes, then radiation and chemotherapy are mandatory.

Stage 2A:

  • For tumors larger than 4 cm, radiation therapy including brachytherapy along with chemotherapy is recommended. Following that, most oncologists suggest hysterectomy.
  • For tumors less than 4 cm, radical hysterectomy can be done. In case of positive surgical margins or histologically positive lymph nodes, then combination of radiation and chemotherapy is indicated.

Stage 2B: Combined internal and external radiation along with chemotherapy (usually cisplatin) is the most common treatment.

Stage 3 and 4A: A combination of radiation and cisplatin chemotherapy is recommended. It is necessary to identify the large infiltrated abdominal lymph nodes by CT or PET in order to be included in the radiation field.

Stage 4B: 

At this stage, cervical cancer has spread out of the pelvis to other sites of the body. Chemotherapy based on cisplatin combined with other drugs is recommended. Radiotherapy may also be administered for pain relief. 

 

Treatment side effects

Side effects of radiation therapy

Radiation may cause short-term as well as long-term side effects. Possible short-term side effects, which usually resolve by the end of treatment, include:

  • Weakness
  • Discomfort with urination
  • Loose stools and frequent bowel movements
  • Temporary loss of pubic hair

Long-term side effects may appear months after treatment is completed and may induce chronic problems. These include:

  • Urine leakage
  • Inflammation of the bowel associated with pain, bleeding and diarrhea
  • Narrowing and drying vagina

 

Side effects of chemotherapy

The most common side effects of chemotherapy are:

  • Weakness
  • Hair loss
  • Nausea and vomiting
  • Diarrhea
  • Low blood counts, bleeding, infections
  • Numbness of fingers and toes.

 

Cervical cancer follow-up

Periodic follow-up examinations are recommended following treatment. There is no established program, but most oncologists recommend:

  • A physical examination every 3 to 4 months for two years, then every 6 months up to 5 years, and annually thereafter.
  • Pap smear annually.
  • Chest x-ray for the first five years annually.

Other tests are not recommended for patients who are asymptomatic. MRI scans may be indicated in special circumstances.

 

Recurrence

Cervical cancer can come back either locally (in the pelvic organs near the cervix) or in distant areas. If the cancer has recurred in the pelvis only, extensive surgery (by pelvic exenteration) may be an option for selected patients. This operation may successfully treat 40% to 50% of patients. Occasionally, palliative radiation or chemotherapy may be used.

If cervical cancer has recurred in a distant area, chemotherapy will be used to treat and relieve specific symptoms. 15% to 25% of patients will respond for some time to chemotherapy.

 

Special considerations

Cervical cancer in pregnancy

Cervical cancers can be found in pregnant women, although they are unusual. In case of very early cancer, such as stage 1A, then most gynecologists feel that it is safe to continue the pregnancy to term. Several weeks after delivery, a hysterectomy or a cone biopsy is recommended.

If the cancer is at stage 1B or more, then the patient and the gynecologist must decide whether to continue the pregnancy. In case of discontinuation, then the treatment would be radical hysterectomy and/or radiation. If the pregnancy is not discontinued, the baby should be delivered by cesarean section as soon as it is able to survive outside the womb. More advanced cancers should be treated immediately. 

Sexual issues

Physical changes following cervical cancer treatment may include vaginal shortening, narrowing, and decreased vaginal lubrication. These physical changes have a significant impact on sexual life because they may lead to pain during intercourse, difficulty having an orgasm, and lack of interest for sexual activity. Using a vaginal moisturizer or lubricant during intercourse can relieve some of these bothersome symptoms. If the vagina is severely narrowed, use of vaginal dilators may help. 

 

Content on this site is not a substitute for professional medical advice. You should always consult your doctor.