Cervical cancer

Cervical cancer

Cancer is the uncontrolled growth of body cells and can start almost anywhere in the human body. When cancer develops in the cervix of female it is termed as cervical cancer or cancer cervix. Cervix is the lower part of the uterus and connects the body of the uterus to the vagina (birth canal).The lower part of the cervix (ectocervix) lies within the vagina and the upper two thirds of the cervix (endocervix) lies above the vagina. Most cervical cancers originate in the area where the endocervix and ectocervix join.

Cervical cancer is the fourth most common cancer in women worldwide and second most common cancer in women living in less developed regions. World Health Organization (WHO) estimated 530 000 new cases of cervical cancer globally (estimations for 2012), with approximately 270 000 deaths (representing 7.5% of all female cancer deaths). More than 85% of these deaths occurred in low- and middle-income countries.

The highest estimated incidence rates for cervical cancer are in sub-Saharan Africa, Melanesia, Latin America and the Caribbean, south-central Asia and south-east Asia.

India has a population of 436.76 million women aged 15 years and older who are at risk of developing cervical cancer. Every year 122844 women are diagnosed with cervical cancer and 67477 die from the disease (estimations for 2012). In India cervical cancer is the second most common cancer among women and also the second most common cancer among women between 15 and 44 years of age.

Nearly all cases of cervical cancer can be attributable to Human papillomavirus (HPV) infection. HPV is a group of viruses and one of the causative agents in the sexually transmitted infections (STIs) in men and women with and without clinical lesions. HPV types (16 and 18) cause 70% of cervical cancers and precancerous cervical lesions worldwide.

Based on Indian studies about 82.7% of invasive cervical cancers showed the presence of HPVs 16 or 18 (Systematic reviews and meta-analyses of the literatures by ICO HPV Information Centre)^*.

Other epidemiological risk factors for cervical cancer are early age at marriage, multiple sexual partners, multiple pregnancies, poor genital hygiene, malnutrition, use of oral contraceptives, and lack of awareness.

India also has the highest (age standardized) incidence rate as 22 (per 100,000 women per year) of cervical cancer in South Asia (estimations for 2012), compared to 19.2 in Bangladesh, 13 in Sri Lanka, and 2.8 in Iran.

Cervical cancer can be prevented by vaccinating all young females against the HPVs and by screening and treating precancerous lesions in women. In addition if cervical cancer is detected early and treated in earlier stages it can be cured.

References-

www.cancer.org/cancer/cervicalcancer/detailedguide/cervical-cancer

* www.hpvcentre.net/statistics/reports/IND.pdf (Human Papillomavirus and Related Diseases Report, India, ICO Information Centre on HPV and Cancer (HPV Information Centre) 2015)

www.who.int/bulletin/volumes/85/9/06-038414/en/

www.who.int/mediacentre/factsheets/fs380/en/

www.who.int/immunization/diseases/hpv/en/

apps.who.int/iris/bitstream/10665/144785/1/9789241548953

Women with early cervical cancers and pre-cancers usually have no symptom. Symptoms of cervical cancer appear only after the cancer has reached an advanced stage. 

Symptoms may be:

• irregular, intermenstrual (between periods) or abnormal vaginal bleeding after sexual intercourse or  bleeding after menopause;
• bleeding after douching, or after a pelvic exam; 
• vaginal discomfort or odorous discharge from vagina, the discharge may contain some blood and may occur between periods or after menopause;
• pain during sex;
• back, leg or pelvic pain;
• fatigue, weight loss, loss of appetite;
• a single swollen leg.

These signs and symptoms are not specific, may be present in other conditions also, but still it is advised to consult health care professional at earliest. More severe symptoms may develop at advanced stages of cervical cancer.

References-

www.who.int/mediacentre/factsheets/fs380/en/

www.webmd.com/cancer/cervical-cancer

There are several risk factors which increase the chances of developing cervical cancer.

The most important risk factor for cervical cancer is infection by the human papillomavirus (HPV).

• HPV is mainly transmitted through sexual contact and most people are infected with HPV shortly after the onset of sexual activity. Skin-to-skin genital contact can transmit the infection; penetrative sex is not required for transmission.
• HPV infections usually clear up without any intervention within a few months after acquiring the infection, and about 90% clear within 2 years.
• A small proportion of infections with certain types of HPV can persist and progress to cancer. The time period between the oncogenic (cancer causing) HPV infection and occurrence of the invasive cervical cancer is 15–20 years.

Risk factors that may lead HPV infection to persist and progress to cancer:

• Early first sexual intercourse
• Multiple sexual partners
• High parity
• Long-term use of hormonal contraceptives
• Tobacco use
• Immune suppression (for example, HIV-infected individuals are at higher risk of HPV infection and are infected by a broader range of HPV types)
• Low socioeconomic status, poor hygiene and diet low in antioxidants
• Co-infection with Chlamydia trachomatis and Herpes simplex virus type-2

References-

www.who.int/mediacentre/factsheets/fs380/en/

www.ncbi.nlm.nih.gov/pmc/articles/PMC3385284/

www.cdc.gov/std/tg2015/hpv.htm

www.who.int/bulletin/volumes/85/9/06-038414/en/

Most of the cervical cancer and HPV infections in the early stages show no clinical signs and symptoms; precancerous lesions and early cancers can be detected by screening tests.

Screening for cervical cancer-There are 3 different types of screening tests:

1. Conventional (Pap) test and liquid-based cytology (LBC) - The Pap test is used to detect abnormal cells that may develop into cancer if left untreated. In a conventional Pap test, the specimen (or smear) is placed on a glass microscope slide and a fixative is added. In an automated liquid-based Pap cytology test, cervical cells collected with a brush or other instrument are placed in a vial of liquid preservative. One advantage of liquid-based testing is that the same cell sample can also be tested for the presence of high-risk types of HPV, a process known as “Pap and HPV co-testing.
2. Visual inspection with acetic acid (VIA) - Doctor may apply a dilute acetic acid solution (vinegar solution) to the cervix, which causes abnormal areas to turn white. Further a biopsy can be taken from abnormal area.
3. HPV testing for high-risk HPV type- HPV testing is used to look for the presence of high-risk HPV types in cervical cells.

• Screening is recommended for every woman from aged 30 to 49 years at least once in a lifetime and ideally more frequently (WHO). Women living with HIV are advised to follow a different screening schedule.
• Women who test negative with VIA or cytology, re-screening is advised at an interval of three to five years; whereas women who test negative with HPV testing, re-screening should be done after a minimum interval of five years.
• If cancer is suspected in women during screening, they should be referred to a facility for diagnosis and treatment of cancer.
• Women who screen positive for cervical pre-cancer can be treated with Cryotherapy or loop electrosurgical excision procedure (LEEP) and should receive post-treatment follow-up after 12 months.

Diagnostic tests for detection of cervical pre-cancer: some times, a diagnostic test is used for definitive diagnosis or confirmation of pre-cancer or cancer subsequent to positive screening results. Colposcopy, biopsy and endocervical curettage (ECC) are the commonly used diagnostic tests for cervical pre-cancer.

• Colposcopy is the examination of the cervix, vagina and vulva with an instrument called colposcope. It is used in patients with positive screening results.
• Biopsy is the removal of small sample of abnormal tissue for microscopic examination. Biopsies can be taken from areas of the cervix that are VIA-positive or from areas that appear suspicious for cancer.
• Endocervical curettage (ECC) is a simple procedure in which some surface cells are gently scraped from the endocervical canal with a special thin instrument or spatula and examined under microscope. An endocervical cytobrush specimen may also be used for examination.

Cervical cancer stages-

• Stage 0: The cancer is found only in the first layer of cells lining the cervix, not in the deeper tissues. The tumor is called carcinoma in situ and not considered to be an invasive cancer.
• Stage I: The cancer has spread from the cervix lining into the deeper tissue but is still just found in the uterus. It has not spread to lymph nodes or other parts of the body.
• Stage II: The cancer has spread beyond the cervix to nearby areas, such as the vagina or tissue near the cervix, but it is still inside the pelvic area. It has not spread to lymph nodes or other parts of the body.
• Stage III: The cancer has spread outside of the cervix and vagina but not to the lymph nodes or other parts of the body.
• Stage IV:  The disease has spread to nearby organs or other parts of the body.

WHO has recommended new guideline for screening and treatment to prevent cervical cancer in July 2021. The new guidelines recommend an HPV DNA based test as the preferred screening test instead of visual inspection with acetic acid (VIA) or Pap smear (cytology). WHO suggests that self-collected samples can be also used when providing HPV DNA testing.

References-

apps.who.int/iris/bitstream/10665/144785/1/9789241548953

www.cancer.gov/types/cervical/pap-hpv-testing-fact-sheet

www.who.int/mediacentre/factsheets/fs380/en/

www.acog.org/~/media/districts/district%20ii/pdfs/uspstf_cervical_

www.cancer.net/cancer-types/cervical-cancer/stages

https://www.who.int/news/item/06-07-2021-new-recommendations-for-screening-and-treatment-to-prevent-cervical-cancer

https://www.who.int/publications/i/item/9789240030824

If abnormal cells or lesions detected during screening tests, treatment is needed to excise them. It includes cryotherapy (destroying abnormal tissue on the cervix by freezing it) or Loop electrosurgical excision procedure (LEEP) when the patient is not eligible for cryotherapy. 

When cancer is diagnosed, the treatment frequently requires a multidisciplinary approach with the involvement of a gynecologic oncologist, radiation oncologist, and medical oncologist. The treatment of cervical cancer varies with the stage of the disease.

• For early invasive cancer, surgery is advised.
• In more advanced cases, radiation combined with chemotherapy and in patients with disseminated disease, chemotherapy or radiation provides palliative management of symptoms.
• Palliative care is given to help people with advanced disease to have dignity and peace during difficult and final phases of life.

References-

apps.who.int/iris/bitstream/10665/94830/1/9789241548694

emedicine.medscape.com/article/253513-treatment

Cervical cancer prevention and control: A comprehensive approach-

WHO recommends a comprehensive approach to cervical cancer prevention and control that includes three interdependent components: primary, secondary and tertiary prevention.

Primary prevention: reduce the risk of HPV infection

It begins with HPV vaccination of girls aged 9-13 years, before they become sexually active. Two HPV vaccines are there - a bivalent and a quadrivalent vaccine.The quadrivalent vaccine gives 100% protection against infection from HPV types 16 and 18, which are responsible for around 70% of all cervical cancers. It also protects against HPV types 6 and 11 that cause genital warts.

The vaccination schedule depends on the age of the vaccine recipient. WHO (March, 2016)^a recommended schedule for both HPV vaccines is as-

• Females <15 years at the time of first dose: a 2-dose schedule (0, 6 months) is recommended. (If the interval between doses is shorter than 5 months, then a third dose should be given at least 6 months after the first dose.)
• Females ≥15 years at the time of first dose: a 3-dose schedule (0, 1-2, 6 months) is recommended.
• 3-dose schedule is recommended for those known to be immunocompromised and/or HIV-infected.

(The vaccines cannot treat HPV infection or HPV-associated disease such as cancer, but it prevents the infection).

Some countries are vaccinating boys for prevention of genital cancers and genital warts in males.

Two vaccines (bivalent and a quadrivalent vaccine), which are licensed in more than a 120 countries, are available in India with the approval of Drug Controller General of India (DCGI). 63 countries have also included HPV vaccination to girls in their national immunization programmes. HPV vaccination for girls is recommended by Indian Academy of Pediatrics (IAP) and Federation of Obstetric and Gynaecological Societies of India (FOGSI) and Cancer foundation of India ^b.

Other preventive interventions may be recommended to boys and girls as appropriate are:

• education about safe sexual practices, including delayed start of sexual activity
• promotion and provision of condoms for those already engaged in sexual activity
• warnings about tobacco use, which often starts during adolescence, and which is an important risk factor for cervical and other cancers, and
• male circumcision.

Male circumcision and the use of condoms have shown a significant protective effect against HPV transmission.

Secondary prevention: screening for and treating pre-cancer

Early detection, by screening all women in the target age group (30-49 years) followed by treatment of detected precancerous lesions can prevent the majority of cervical cancers. Cervical cancer screening should be an essential part of a woman’s routine health care. It detects pre-cancer and cancer among women who have no symptoms and may feel perfectly healthy. Important aspect of screening is that both precancerous lesions and early cervical cancers can be treated very successfully at this stage.

Tertiary prevention: treatment of invasive cervical cancer

The goal of tertiary prevention is to decrease the number of deaths due to cervical cancer. Women suspected of having invasive cervical cancer should be referred to facilities that offer cancer diagnosis and treatment. Appropriate treatment in early stage of cancer can result in cure. In advanced stage of cancer treatment and palliative care can improve quality of life, control symptoms and minimize pain suffering.

Five key messages (WHO)^c :

1. Cervical cancer is a disease that can be prevented.
2. There are tests to detect early changes in the cervix (known as pre-cancers) that may lead to cancer if not treated.
3. There are safe and effective treatments for these early changes.
4. All women aged 30–49 years should be screened for cervical cancer at least once.
5. There is a vaccine for girls that can help prevent cervical cancer.

New strategies for screening and treatment of cervical pre-cancer lesions for cervical cancer prevention by WHO:

The World Health Organization (WHO) has recommended the new guidelines for screening and treatment to prevent cervical cancer in July 2021. The new guidelines recommend an HPV DNA based test as the preferred test as primary screening test instead of visual inspection with acetic acid (VIA) or Pap smear (cytology).

For the general population of women-

Screen and Treat or Screen, Triage and Treat:

• HPV DNA as primary screening test
• Starting at the age of 30 years
• Every 5-10 years screening interval

For women living with HIV:

Screen, triage and treat –only

• HPV DNA as primary screening test

• starting at the age of 25
• with regular screening every 3 to 5 years.

(Screening and treatment approaches:

• In the “screen-and-treat approach”, the decision to treat is based on a positive primary screening test only.
• In the “screen, triage and treat approach”, the decision to treat is based on a positive primary screening test followed by a positive second test (a “triage” test), with or without histologically confirmed diagnosis)

References-

awww.who.int/immunization/diseases/hpv/en/

b. www.cancerfoundationofindia.org/meeting

c.apps.who.int/iris/bitstream/10665/144785/1/9789241548953

apps.who.int/iris/bitstream/10665/94830/1/9789241548694

www.who.int/mediacentre/factsheets/fs380/en/

https://www.who.int/news/item/06-07-2021-new-recommendations-for-screening-and-treatment-to-prevent-cervical-cancer

https://www.who.int/publications/i/item/9789240030824