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:
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. In 2017, there was an estimated 1550 new cases and approximately 400 deaths. About 12% of cervical cancers continue to be diagnosed at stage IV, with the highest incidence rate among women aged 55 years and older . 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 .
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%) .
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.
- Co-infection with chlamydia can make it more difficult to clear HPV infection
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).
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.
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.
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.
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.
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).
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 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.
Ask about timing and duration of symptoms:
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.
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.
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
2. Low grade intraepithelial lesions (LSIL)
3. High grade intraepithelial lesions (HSIL)
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)
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.
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.
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.
Cone biopsy (conization)
Loop Electrosurgical Excision (LEEP)
Sentinel Lymph Node Biopsy (SLNB)
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 .
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 .