Tap icon
to view sections

Objectives

The following module was designed following the objectives of the Oncology Goals and Objectives for Medical Students for cervical cancer. Information on epidemiology, risk factors, prevention, screening, presentation, diagnosis, and treatment for cervical cancer is provided. By the end of this module, the following objectives should be addressed:

  1. Understand the epidemiology of cervical cancer in Canada.
  2. Identify common risk factors associated with cervical cancer.
  3. Describe cervical cancer prevention strategies.
  4. Understand the current recommendations for cervical cancer screening in Canada.
  5. Understand the basic anatomy of the cervix.
  6. Describe the signs and symptoms of cervical cancer.
  7. Describe the approach to cervical cancer diagnosis. 
  8. Describe the different modalities used in treatment, and their indications.

Epidemiology

Cervical cancer is the 3rd most common malignancy worldwide and ranks 13th in incidence in Canada, accounting for 2% of all new cancer cases in women[1][2][3]. In 2017, there was an estimated 1550 new cases and approximately 400 deaths[4].  About 12% of cervical cancers continue to be diagnosed at stage IV, with the highest incidence rate among women aged 55 years and older [3]. However, the majority 54% percent of cervical cancers were diagnosed at stage I, with more than 70% of those diagnoses in females ages 18-39 years. Since the 1980’s, the age-adjusted incidence rate has fallen dramatically, and since 2009 it continues to fall steadily by 3% per year. Organized cervical cancer screening programs are largely responsible for this high detection rate and fall in incidence [3]. 

The five-year survival for cervical cancer is about 73% in Canada. Higher survival rates have been described in the United States for localized cancers (86%) versus those with regional involvement (56%) and distant metastases (17%) [3].

Risk Factors

Human Papillomavirus Virus Exposure (HPV)

HPV is a small DNA virus and is the most important risk factor for cervical cancer. About 90-95% of women with cervical cancer are HPV positive. HPV can infect cells lining the genitals, anus, mouth and throat. It spreads by skin-to-skin contact through micro-abrasions from one person to another. Commonly, it is spread via sexual activity including vaginal, anal, oral, and digital sex.

There are more than 100 HPV related strains. Some are coined low-risk strains of HPV like types 6 and 11 because most people are able to clear the infection and they seldom result in cancer. These aforementioned strains often cause genital warts. Other strains called high-risk types of HPV, such as 16, 18, 31, and 33, cause chronic infection leading to cancer of the cervix and others including vuvla and vagina in women.

HPV is the most common sexually transmitted infection, with over 80% of men and women being infected at some point in their life. Certain patterns of sexual behaviour have been associated with an increased risk of genital HIV acquisition, which consequently increases the risk of cervical cancer.


The following increases HPV Exposure:

1. Sexual Exposure
  • Early age of first coitus
  • Multiple sexual partners
  • History of sexually transmitted diseases

            - Co-infection with chlamydia can make it more difficult to clear HPV infection

  • Partner has cervical cancer or is in contact with partner with cervical cancer 

The following increases the likelihood of persistent infection resulting in cancer:

2. Immunocompromised
  • Steroids, smoking, renal failure, diabetes, HIV
3. Smoking
  • Smoking is also known to directly damage the DNA of cervical cells   contributing to the development of cervical cancer

Other risk factors:

4. Multiparity
5. Low Socioeconomic class
  • Less access to health care services including pap screening programs
6. Long term oral contraceptive use
7. Prenatal exposure to diethylstilbestrol (DES)
  • DES is a form of estrogen used between 1940 to 1971 during pregnancy to prevent miscarriage. Daughters of women who took DES during pregnancy have a higher risk of developing a rare type of cervical cancer, clear cell adenocarcinoma. They also have a higher risk of developing precancerous changes of the cervix or squamous cell cancer. Disapproved for use in pregnancy since 1970s. 

Prevention

Primary

Prevention is challenging in sexually active adults because HPV can be present in areas not covered by a latex condom, limiting its effectiveness. Those infected are often asymptomatic and further transmit the virus unknowingly. The primary prevention measure is receiving the HPV vaccination, as this will convey the greatest benefit prior to onset of sexual activity. However, most people up to the age of 45, which is the upper cut off for vaccination, will benefit from some form of vaccination as it is less likely that one person will be exposed to multiple HPV strains. Those who are immunocompromised, such as those with HIV positive status, are highly recommended to receive vaccination. 

There are three types of vaccines offered depending on age and coverage: HPV2, HPV4, and HPV9, which protects against two, four and nine HPV strains respectively.  Specially, the HPV2 vaccine (known as Cervarix®), is indicated for females aged 9-45 years of age, and HPV4/HPV9 (known as Gardasil®, and Gardasil®9 respectively) are indicated for females aged 9-45 years of age, and males aged 9-26 years of age. Cervarix® and Gardasil® prevents 70% of all cervical cancers, providing protection for high-risk HPV types 16 and 18 while Gardasil® prevents infection HPV 6 and 11 strains as well, which cause 90% of genital warts. Gardasil®9 prevents infection with the same four HPV types in addition to five additional cancer-causing types, that together account for 90% of cervical cancers (HPV types 6, 11, 16, 18, 31, 33, 45, 52, 58).

Secondary 

The long natural history of HPV infection and cervical dysplasia means it is highly preventable and treatable. Secondary prevention through screening programs is highly recommended and includes regular papanikolaou (pap) smear testing for women in Canada. There is some variation in cervical cancer screening guidelines between province. In general, provinces recommend that cervical screening begin at age twenty-one or twenty-five, continue to age 65 to 70 and occur every two to three years. Nunavut, Northwest Territories, and the Yukon do not not have a screening program, and with the exception of Quebec, all other provinces have organized screening programs available. 

A pap test removes a small sample of cells from the squamo-columnar junction (SCJ) of the cervix, where most cancerous changes arise. These cells are viewed under a microscope to determine whether there are any abnormal pre-cancerous or cancerous changes present. By treating these cells early, cervical cancer can be stopped from developing. Pap tests can reduce your risk of developing cervical cancer by up to 70%. However, due to the low sensitivity (55-60% ) of pap smear testing, it will need to be repeated every 3 years. Please visit https://canadiantaskforce.ca/tools-resources/cervical-cancer-2/cervical-cancer-patient-algorithm/for more information regarding screening in Canada.

Squamocolumnar Junction

The SCJ is between the endocervical (closest to the uterine cavity) columnar epithelium and ectocervical (closest to the vagina lumen) stratified squamous epithelium. This junction is a site of continuous transformation where the columnar epithelium undergoes gradual transition to the squamous epithelium of the ectocervix with hormone status during a woman’s reproductive life.  The anatomical location of this transformation zone and SCJ is not constant throughout a woman’s life. As the woman ages, from birth to menopause, the SCJ involutes, moving towards the cervical os, higher into the endocervical canal. The transformation zone becomes larger and a normally occurring region of metaplasia. This transformation zone may also undergo further malignant changes, being a site for cervical cancer.

Seeing that the transformation zone may undergo malignant changes, the pap smear aims to sample the cells from this zone. An adequate pap smear includes a sample from both the columnar epithelium of the endocervix, as well as the squamous epithelium of the ectocervix.

Figure 1. Cervical Transformation Zone

HPV testing is performed to detect those who have an active HPV infection, however, this modality is not used for primary screening and currently only used to risk stratify patients after treatment for cervical dysplasia in some provinces and territories. This testing modality is highly sensitive (94%), thereby only needing repeat testing every 5 years. Nonetheless, there continues to be challenges in transitioning to this different screening paradigm. Ontario is actively planning the implementation of HPV testing for primary screening, and British Columbia has it under consideration. Private pay options in British Columbia exist to use this testing modality as a primary preventative measure. 

Screening Guidelines in Canada

Cervical Cancer 2013 Screening Guidelines 

The following recommendations are made by the Canadian Task Force on Preventive Health Care which serves as the basis of most screening programs in Canada. The provinces of British Columbia and Alberta have adopted the later screening start age of 25 years in 2016, and Nova Scotia adopted this change in 2019. Ontario, Prince Edward Island, and Newfoundland are still in the consideration phase of changing the screening start age. 

These guidelines do not apply to women with symptoms (e.g., vaginal bleeding), women with previous abnormal results on screening (and who have not been cleared to return to normal screening), women who do not have a cervix and women who are immunocompromised. 

Table 1. Cervical Generalized Screening Guidelines
Table 2. Provincial and Territorial Screening Guidelines

Anatomy

The cervix forms the inferior part of the uterus, shaped like a short cylinder with a central channel.  The central canal of the cervix opens below as the external os, into the vaginal cavity. Where the end of the cervix meets the upper portion of the vaginal wall a fornix is formed. The internal os is the central canal between the lower aspect of the uterus and upper aspect of the cervix (Gray’s basic anatomy). 

The internal iliac artery is the major artery that supplies the pelvis and perineum. It originates from the common iliac artery [not shown here] on each side. It divides into the anterior and posterior trunk, with the anterior trunk supplying the pelvic viscera, the perineum, gluteal region, and the adductor region of the thigh. The uterine artery is the third vessel to come off the anterior trunk of the internal iliac artery, and it courses medially and anteriorly to the base of the broad ligament to reach to the cervix, it moves up along the lateral side of the uterus to reach the uterine tube, where it curves laterally and anastomoses with the  ovarian artery (Gray’s basic anatomy). 

Figure 2. Fallopian tube, uterus, cervix, and vagina
Figure 3. Female reproductive system with arterial supply

Signs and Symptoms

Many patients are asymptomatic but some occasionally present with abnormal vaginal bleeding. Some report post-coital bleeding or bleeding after a pelvic exam or douching. These symptoms are related to spontaneous tumour bleeding or after irritation of the tumour. More advanced lesions may present with increased vaginal discharge that may be watery, mucoid, or purulent and malodorous. With direct invasion to neighbouring organs, such as the bowel and bladder, we may see presentations such as pressure related bowel symptoms, as well as hematuria, hematochezia and vaginal passage of urine or stool. Depending on the tissues and organs to which the disease has spread, symptoms and severity will vary. For example, pelvic or back pain that may go down one or both legs can occur in advanced disease that has spread to the spine. General signs of cancer progression include loss of appetite, weight loss, shortness of breath, coughing up blood, chest or bone pain and fatigue.

Diagnosis

Diagnosis of cervical cancer can be underway from an abnormal pap smear result or through the traditional approach beginning with a thorough history and physical exam, followed by investigations.

A) Traditional Approach

History

Ask about timing and duration of symptoms:

  • Bleeding, dyspareunia
  • Back pain and pelvic pressure
  • Bladder or bowel changes
  • Pap smear history
  • Risk factors

Physical

Perform a speculum examination to carefully inspect the cervix, entire vulva, and vagina.  Most women have a visible cervical lesion with local disease. Squamous cell carcinoma usually originates at SCJ, and It may look like a superficial ulceration, or exophytic tumor. There might be infiltration into the endocervix, and some adenocarcinomas can be hidden in the endocervical canal.

Next, palpate the cervix. Does the cervix pull off to one side (sign of surrounding tissue (parametrial) extension - felt with rectal finger)? Is the cervix bulky? (i.e., > 4cm). Is the disease fixed (indication of invasion of pelvic side wall)? Lastly, perform a rectovaginal exam.  A complete physical exam includes a general examination for signs of metastases with care to inspect the supraclavicular, inguinal, and femoral lymph nodes.

Labs

  • CBC, Cr, LFTs, electrolytes (alk phos if bone pain)
  • HIV if risk factors
  • CEA not reliable
  • CA125 elevated in only 20% (more often with adenocarcinoma)

Imaging (diagnosis and staging) 

  • CXR
  • CT abdo and pelvis
  • MR more sensitive for detection of nodal disease and surrounding tissue invasion (parametrial), likely better at detecting bladder or rectal wall involvement. Required prior to initiating radiotherapy. 
  • Cystoscopy if bladder invasion suspected
  • Proctosigmoidoscopy if rectal invasion suspected 
  • Bone imaging if symptomatic
  • PET scan is  highly sensitive (85 - 90%) and specific (95 - 100%) for detection of malignant adenopathy in patients with locally advanced cervical cancer. Prior to initiating radiotherapy, a PET scan is required for planning/staging purposes. 

Diagnosis is based on histological findings. If there is suspicion of cervical cancer, colposcopy and cervical biopsy is required, and can be performed under anesthesia.

B) Abnormal Screening Pap Smear Result

An abnormal pap smear result can indicate pre-cancer, carcinoma in situ or cancer which can prompt further testing including colposcopy with biopsy. Pap smears are analyzed based on the Bethesda classification system. The following are the abnormalities that can be classified in a pap smear based on the Bethesda system:

1. Atypical squamous cells

  • Atypical squamous cells of undetermined significance (ASC-US)
  • Atypical squamous cells – cannot exclude HSIL (ASC-H)

2. Low grade intraepithelial lesions (LSIL)

  • Indicates mild dysplasia.

3. High grade intraepithelial lesions (HSIL)

  • Indicates moderate to severe dysplasia or carcinoma in situ

4. Squamous cell carcinoma

5. Atypical glandular cells not otherwise specified (AGC-NOS)

6. Atypical glandular cells, suspicious for AIS or cancer (AGC-neoplastic)

7. Adenocarcinoma in situ (AIS)

Table 3. Abnormal Pap Smear Result


Colposcopy – The vagina and cervix are examined via a magnifying instrument called a colposcope. Magnification allows for a more accurate identification of the type and extent of abnormal cells.

Biopsy – Sampling of suspicious area (lesion, tissue) so that cells can be examined with a microscope or other tests.

Histopathology classification:

The Cervical intraepithelial neoplasia (CIN) system is a histological classification system used for cervical biopsies that correlates to the Bethesda system of evaluating an abnormal pap smear result.

  • CIN I refers to cellular dysplasia confined to the basal third of the epithelium (formerly mild dysplasia).
  • CIN II refers to lesions confined to the basal two-thirds of the epithelium (formerly moderate dysplasia).
  • CIN III refers to cellular dysplasia encompassing greater than two-thirds of the epithelial thickness, including full-thickness lesions (formerly severe dysplasia and CIS). 
CIN is Characterized by:
  1. Cellular immaturity
  2. Cellular disorganization
  3. Nuclear abnormalities
  4. Increased mitotic activity

Treatment

Treatment is based on staging, with lower stages managed surgically, and higher stages often needing treatment with radiation and chemotherapy.

Staging was not discussed in detail in this module. It takes into consideration the histological characteristic of the lesion, and extent of invasion including local, lymph node and distant metastasis. Treatment is broadly dictated by stage, but it is often tailored to the individual case. Cervical tumours are staged using the Federation of Gynecology and Obstetrics (FIGO) and the Union for International Cancer Control (UICC) TNM staging classifications. Below we provide a broad overview of treatment options based on the FIGO classification system. 

Table 4. Treatment Overview by Stage

Cone biopsy (conization)

  • A cone-shaped sample of tissue is removed from the cervix using a scalpel or laser.
  • Used for treatment when the precancerous cells are too far up the cervical canal to be reached with other methods.
  • Usually requires hospital day surgery, done under local anesthetic.
  • Increased but small risk of future pregnancy problems.

Loop Electrosurgical Excision (LEEP)

  • A fine wire loop electrode is used to remove the transformation zone.
  • Done in a physician's office or clinic, with a local anesthetic.
  • Increased but small risk of future pregnancy problems.

Laser

  • A high-energy beam of light is used to vaporize the abnormal cells.
  • Extremely precise and minimal effect on the surrounding normal tissue.
  • Done in a clinic, without the need for local anesthesia.
  • Patients may experience a sensation of heat or warmth, but this passes rapidly as the procedure is completed.
  • More rapid healing compared to other treatment methods.
  • Unlikely to affect a woman's fertility or ability to carry a pregnancy.
  • Not recommended during pregnancy.
  • If a biopsy (sample) specimen is required, laser is not recommended.

Trachelectomy 

  • Surgical removal of the cervix, the upper vagina and surrounding supportive tissues (parametrium). 

Hysterectomy

  • Surgical removal of the cervix, uterus and sometimes the fallopian tubes and ovaries.
  • Chosen under certain circumstances, and for women who have other gynecological conditions, for which a hysterectomy is an appropriate treatment option, and who do not want to have future pregnancies.

Sentinel Lymph Node Biopsy (SLNB)

  • A SLNB is used to determine if the cancer has spread to lymph nodes. 
  • A radioactive substance/blue dye will be injected close to the area of the tumour and it is absorbed by the lymph vessels, consequently moving to the lymph nodes closest to the tumour.
  • The surgeon uses a special probe to find the radioactive lymph node, or looks for lymph node(s) stained blue by the dye and removes the sentinel lymph node(s).
  • The sentinel lymph node is examined under a microscope for abnormal cells.

Initial follow-up is generally undertaken by an endocrinologist, surgeon, or at a cancer centre. Thereafter, most patients are referred back to the care of their family physician [5].

The follow-up is variable from centre to centre and from patient to patient, however, generally it is recommended a visit every 3 to 4 months for the first two years. If there is no evidence of recurrence after 2 years then visits should be every 6 months for the next two years, with annual visits thereafter.

Initial investigations may include neck ultrasonography (every 6 - 12 months), TSH levels, and serum thyroglobulin (Tg) levels on thyroid hormone suppression (every 3 to 6 months for the first year). Iodine scanning is typically continued until there is no evidence of uptake in the neck or elsewhere and only repeated if the thyroglobulin starts to rise of recurrence or metastasis is clinically detected.

If a patient is high risk and demonstrate either a biochemical or structural incomplete response to therapy, additional imaging can be considered, including MRI, CT, and FDG-PET. Gross residual disease in cervical lymph nodes identified by physical examination or ultrasonography should be confirmed by FNA and surgical resection considered. Diagnostic whole-body radioiodine scanning may have a role in the follow-up of patients with high or intermediate risk.

Most recurrences of differentiated thyroid cancer occur within the first five years after initial treatment, however, recurrences may occur many years or even decades later, particularly in patients with papillary cancer. Therefore, ongoing follow-up after one year post-treatment is guided by individual assessment of the patient’s response to therapy during the first year of follow-up [5].

References

Epidemiology, Risk Factors, Prevention

  1. American Cancer Society. (2017). What Are the Risk Factors for Cervical Cancer? Retrieved from: https://www.cancer.org/cancer/cervical-cancer/causes-risks-prevention/risk-factors.html
  2. BC Cancer. (2019). BC cancer screening cervix. Retrieved from: http://www.bccancer.bc.ca/screening/cervix
  3. Canadian Cancer Society. (2019). Risk factors for cervical cancer. Retrieved from: http://www.cancer.ca/en/cancer-information/cancer-type/cervical/risks/?region=on
  4. Canadian Cancer Society. (2018). Canadian Cancer Statistics. Retrieved from: http://www.cancer.ca/~/media/cancer.ca/CW/cancer%20information/cancer%20101/Canadian%20cancer%20statistics/Canadian-Cancer-Statistics-2018-EN.pdf?la=en 
  5. Canadian Cancer Society. (2019). Cervical cancer statistics. Retrieved from: http://www.cancer.ca/en/cancer-information/cancer-type/cervical/statistics/?region=on 
  6. Globocan cancer fact sheet. (2011). Retrieved from: http://globocan.iarc.fr/factsheets/cancers/cervix.asp.
  7. Government of Canada. (2017). Human Papillomavirus (HPV) Prevention and HPV Vaccines: Questions and Answers. Retrieved from: https://www.canada.ca/en/public-health/services/infectious-diseases/sexual-health-sexually-transmitted-infections/hpv-prevention-vaccines-questions-answers.html#a1
  8. Government of Canada. (2009). Cervical Cancer Facts and Figures. Retrieved from: https://www.canada.ca/en/public-health/services/chronic-diseases/cancer/cervical-cancer-facts-figures.html

Screening Guidelines in Canada

  1. Canadian Task Force on Preventive Health Care. (2013). Recommendations on screening for cervical cancer. Canadian Medical Association Journal. 
  2. Canadian Partnership Against Cancer. Cervical Cancer Screening in Canada: Environmental Scan. Toronto: Canadian Partnership Against Cancer; 2018. Retrieved from: https://www.cancerview.ca/wp-content/uploads/2019/01/Cervical-Cancer-Screening-Environmental-Scan_EN_2018.pdf
  3. BC Cancer Agency. (2017). Cervical cancer screening program. Retrieved from: http://www.bccancer.bc.ca/screening/documents/ccsp_guidelinesmanual-screeningforcancerofthecervix.pdf and see section on Screening recommendations for individuals at High Risk of Developing Cervical Cancer
  4. BC Cancer Agency. (2017). Screening for Cancer of the Cervix. Retrieved from: http://www.bccancer.bc.ca/screening/documents/ccsp_guidelinesmanual-screeningforcancerofthecervix.pdf

Anatomy

  1. Drake, R. L., Vogl, W., & Mitchell, A. W. M. (2012). Grays basic anatomy. Philadelphia, PA: Elsevier.
  2. Henry Vandyke Carter - Henry Gray (1918) Anatomy of the Human Body (See "Book" section below)Bartleby.com: Gray's Anatomy, Plate 1170, Public Domain, https://commons.wikimedia.org/w/index.php?curid=567147

Diagnosis 

  1. Ingledew, P. (!). Cervix Review Notes.
  2. Klopp AH, Eifel PJ, Berek JS, Konstantinopoulos PA. Cancer of the cervix, vagina and vulva. DeVita VT Jr, Lawrence TS, Rosenberg SA. (2015). Cancer: Principles and Practice of Oncology. (10th Edition). Philadelphia: Wolters Kluwer Health/Lippincott Williams & Wilkins. 72:1013-1047.
  3. Levine DA, Dizon DS, Yashar CM, Barakat RR, Berchuch A, Markman M, Randall ME. (2015). Handbook for Principles and Practice of Gynecologic Oncology. (2nd Edition). Philadelphia, PA: Wolters Kluwer.
  4. National Cancer Institute. (2018). Cervical Cancer Treatment (PDQ®) Health Professional Version. Retrieved from: http://www.cancer.gov/.
  5. Oleszewski K. Cervical cancer. Yarbro CH, Wujcki D, Holmes Gobel B, (eds.). (2018). Cancer Nursing: Principles and Practice. (8th Edition). Burlington, MA: Jones and Bartlett Learning. 50: 1397 - 1421.
  6. US National Library of Medicine. (2017). MedlinePlus Medical Encyclopedia: Cervical cancer. Retrieved from: https://medlineplus.gov/ency/article/000893.htm.

Treatment

  1. Cervix. (2016). BC Cancer Agency.http://www.bccancer.bc.ca/health-info/types-of-cancer/womens-cancer/cervix
  2. FIGO staging for carcinoma of the vulva, cervix, and corpus uteri. (2014). International Journal of Gynecology & Obstetrics, 125(2), 97–98. doi: 10.1016/j.ijgo.2014.02.003
  3. Marth, C., Landoni, F., Mahner, S., Mccormack, M., Gonzalez-Martin, A., & Colombo, N. (2017). Cervical cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up†. Annals of Oncology, 28(suppl_4), iv72–iv83. doi: 10.1093/annonc/mdx220
  4. Mello V, Sundstrom RK. Cancer, Cervical Intraepithelial Neoplasia (CIN) [Updated 2019 Jun 16]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2019 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK544371/

Whiteboard Videos

Coming soon