General Information About Cervical Cancer
Cervical cancer is the fourth most common cancer in women worldwide, and it has the fourth highest mortality rate among cancers in women. Most cases of cervical cancer are preventable by routine screening and by treatment of precancerous lesions. As a result, most of the cervical cancer cases are diagnosed in women who live in regions with inadequate screening protocols.
Incidence and Mortality
Estimated new cases and deaths from cervical (uterine cervix) cancer in the United States in 2018:
- New cases: 13,240.
- Deaths: 4,170.
The uterine cervix is contiguous with the uterine body, and it acts as the opening to the body of the uterus. The uterine cervix is a cylindrical, fibrous organ that is an average of 3 to 4 cm in length. The portio of the cervix is the part of the cervix that is visible on vaginal inspection. The opening of the cervix is termed the external os. The os is the beginning of the endocervical canal, which forms the inner aspect of the cervix. At the upper aspect of the endocervical canal is the internal os, a narrowing of the endocervical canal. The narrowing marks the transition from the cervix to the uterine body. The endocervical canal beyond the internal os is termed the endometrial canal.
The cervix is lined by two types of epithelial cells: squamous cells at the outer aspect, and columnar, glandular cells along the inner canal. The transition between squamous cells and columnar cells is an area termed the squamo-columnar junction. Most of precancerous and cancerous changes arise in this zone.
Cervical carcinoma has its origins at the squamous-columnar junction; it can involve the outer squamous cells, the inner glandular cells, or both. The precursor lesion is dysplasia: cervical intraepithelial neoplasia (CIN) or adenocarcinoma in situ, which can subsequently become invasive cancer. This process can be quite slow. Longitudinal studies have shown that in patients with untreated in situ cervical cancer, 30% to 70% will develop invasive carcinoma over a period of 10 to 12 years. However, in about 10% of patients, lesions can progress from in situ to invasive in a period of less than 1 year. As it becomes invasive, the tumor breaks through the basement membrane and invades the cervical stroma. Extension of the tumor in the cervix may ultimately manifest as ulceration, exophytic tumor, or extensive infiltration of underlying tissue, including the bladder or rectum.
Increasing age is the most important risk factor for most cancers. The primary risk factor for cervical cancer is human papillomavirus (HPV) infection.[3-6]
Other risk factors for cervical cancer include the following:
- High parity and HPV infection.
- Smoking cigarettes and HPV infection.
- Long-term use of oral contraceptives and HPV infection.[9,10]
- Having first sexual encounter at a young age.
- High number of sexual partners.
- Exposure to diethylstilbestrol (DES) in utero.
Human papillomavirus (HPV) infection
HPV infection is a necessary step in the development of virtually all precancerous and cancerous lesions. Epidemiologic studies convincingly demonstrate that the major risk factor for development of preinvasive or invasive carcinoma of the cervix is HPV infection, far outweighing other known risk factors.
More than 6 million women in the United States are estimated to be infected with HPV. Transient HPV infection is common, particularly in young women, while cervical cancer is rare. The persistence of an HPV infection leads to increased risk of developing precancerous and cancerous lesions.[16,17]
The strain of HPV infection is also important in conferring risk. There are multiple subtypes of HPV that infect humans; of these, subtypes 16 and 18 have been most closely associated with high-grade dysplasia and cancer. Studies suggest that acute infection with HPV types 16 and 18 conferred an 11-fold to 16.9-fold risk of rapid development of high-grade CIN.[18-20] Further studies have shown that infection with either HPV 16 or 18 is more predictive than cytologic screening of high-grade CIN or greater disease, and that the predictive ability is seen for up to 18 years after the initial test.[21-23]
There are two commercially available vaccines that target anogenital-related strains of HPV. The vaccines are directed towards HPV-naïve girls and young women, and although penetration of the vaccine has been moderate, significant decreases in HPV-related diseases have been documented. (Refer to the PDQ summary on Cervical Cancer Prevention for more information.)
Early cervical cancer may not cause noticeable signs or symptoms.
Possible signs and symptoms of cervical cancer include the following:
- Vaginal bleeding.
- Unusual vaginal discharge.
- Pelvic pain.
- Postcoital bleeding.
The following procedures may be used to diagnose cervical cancer:
- History and physical exam.
- Pelvic exam.
- Cervical cytology (Pap smear).
- HPV test.
- Endocervical curettage.
Cervical cytology (Pap smear) has been the mainstay of cervical cancer screening since its introduction. However, molecular techniques for the identification of HPV DNA are highly sensitive and specific. Current screening options include the following:
- Cytology alone.
- Cytology and HPV testing.
HPV testing is suggested when it is likely to successfully triage patients into low- and high-risk groups for a high-grade dysplasia or greater lesion.
HPV DNA tests are unlikely to separate patients with low-grade squamous intraepithelial lesions into those who do and those who do not need further evaluation. A study of 642 women found that 83% had one or more tumorigenic HPV types when cervical cytologic specimens were assayed by a sensitive (hybrid capture) technique. The authors of the study and of an accompanying editorial concluded that using HPV DNA testing in this setting does not add sufficient information to justify its cost.
HPV DNA testing has proven useful in triaging patients with atypical squamous cells of undetermined significance to colposcopy and has been integrated into current screening guidelines.[25-27]
Other studies show that patients with low-risk cytology and high-risk HPV infection with types 16, 18, and 31 are more likely to have CIN or microinvasive histopathology on biopsy.[18,28-30] One method has also shown that integration of HPV types 16 and 18 into the genome, leading to transcription of viral and cellular messages, may predict patients who are at greater risk for high-grade dysplasia and invasive cancer.
For women older than 30 years who are more likely to have persistent HPV infection, HPV typing can successfully triage women into high- and low-risk groups for CIN 3 or worse disease. In this age group, HPV DNA testing is more effective than cytology alone in predicting the risk of developing CIN 3 or worse. Other studies have shown the effectiveness of a primary HPV DNA–screening strategy with cytology triage over the previously used cytology-based screening algorithms.[33,34]
The prognosis for patients with cervical cancer is markedly affected by the extent of disease at the time of diagnosis. More than 90% of cervical cancer cases can be detected early through the use of the Pap test and HPV testing. Pap and HPV testing are not performed on approximately 33% of eligible women, which results in a higher-than-expected death rate.
Clinical stage as a prognostic factor is supplemented by several gross and microscopic pathologic findings in surgically treated patients.
Evidence (clinical stage and other findings):
In a large, surgicopathologic staging study of patients with clinical stage IB disease reported by the Gynecologic Oncology Group (GOG) (GOG-49), the factors that most prominently predicted for lymph node metastases and a decrease in disease-free survival were capillary-lymphatic space involvement by tumor, increasing tumor size, and increasing depth of stromal invasion, with the latter being the most important and reproducible.[36,37]
In a study of 1,028 patients treated with radical surgery, survival rates correlated more consistently with tumor volume (as determined by precise volumetry of the tumor) than with clinical or histologic stage.
A multivariate analysis of prognostic variables in 626 patients with locally advanced disease (primarily stages II, III, and IV) studied by the GOG identified the following variables that were significant for progression-free interval and survival:
- Periaortic and pelvic lymph node status.
- Tumor size.
- Patient age.
- Performance status.
- Bilateral disease.
- Clinical stage.
The study confirmed the overriding importance of positive periaortic nodes and suggested further evaluation of these nodes in locally advanced cervical cancer. The status of the pelvic nodes was important only if the periaortic nodes were negative. This was also true for tumor size.
It is controversial whether adenocarcinoma of the cervix carries a significantly worse prognosis than squamous cell carcinoma of the cervix. Several population-based and retrospective studies show a worse outcome for patients with adenocarcinoma, with an increase in distant metastasis noted, when compared with those with squamous histology.[41-44] Reports conflict about the effect of adenosquamous cell type on outcome.[45,46] One report showed that approximately 25% of apparent squamous tumors have demonstrable mucin production and behave more aggressively than their pure squamous counterparts, suggesting that any adenomatous differentiation may confer a negative prognosis.
In a large series of cervical cancer patients treated by radiation therapy, the incidence of distant metastases (most frequently to the lung, abdominal cavity, liver, and gastrointestinal tract) was shown to increase as the stage of disease increased, from 3% in stage IA to 75% in stage IVA. A multivariate analysis of factors influencing the incidence of distant metastases showed stage, endometrial extension of tumor, and pelvic tumor control to be significant indicators of distant dissemination.
GOG studies have indicated that prognostic factors vary depending on whether clinical or surgical staging are utilized and with different treatments. Delay in radiation delivery completion is associated with poorer progression-free survival when clinical staging is used. To-date, stage, tumor grade, race, and age are uncertain prognostic factors in studies utilizing chemoradiation.
Other prognostic factors
Other prognostic factors that may affect outcome include the following:
- Human immunodeficiency virus (HIV) status: Women with HIV have more aggressive and advanced disease and a poorer prognosis.
- C-myc overexpression: A study of patients with known invasive squamous carcinoma of the cervix found that overexpression of the C-myc oncogene was associated with a poorer prognosis.
- Number of cells in S phase: The number of cells in S phase may also have prognostic significance in early cervical carcinoma.
- HPV-18 DNA: HPV-18 DNA has been found to be an independent adverse molecular prognostic factor. Two studies have shown a worse outcome when HPV-18 was identified in cervical cancers of patients undergoing radical hysterectomy and pelvic lymphadenectomy.[53,54]
- A polymorphism in the Gamma-glutamyl hydrolase enzyme, which is related to folate metabolism, has been shown to decrease response to cisplatin, and as a result is associated with poorer outcomes.
Follow-up After Treatment
High-quality studies are lacking, and the optimal treatment follow-up for patients after treatment for cervical cancer is unknown. Retrospective studies have shown that patients who recur are most likely to do so within the first 2 years. As a result, most guidelines suggest routine follow-up every 3 to 4 months for the first 2 years, followed by evaluations every 6 months. Most recurrences are diagnosed secondary to new patient symptoms and signs,[57,58] and the usefulness of routine testing including a Pap smear and chest x-ray is unclear.
Follow-up should be centered around a thorough history and physical examination with a careful review of symptoms; imaging should be reserved for evaluation of a positive finding. Patients should be asked about possible warning signs, including the following:
- Abdominal pain.
- Back pain.
- Painful or swollen leg.
- Problems with urination.
The follow-up examination should also screen for possible complications of previous treatment because of the multiple modalities (surgery, chemotherapy, and radiation) that patients often undergo during their treatment.
Other PDQ summaries containing information related to cervical cancer include the following:
- Ferlay J, Soerjomataram I, Ervik M, et al.: GLOBOCAN 2012 v1.0, Cancer Incidence and Mortality Worldwide. Lyon, France: International Agency for Research on Cancer, 2013. IARC CancerBase No. 11. Available online. Last accessed August 2, 2018.
- American Cancer Society: Cancer Facts and Figures 2018. Atlanta, Ga: American Cancer Society, 2018. Available online. Last accessed August 3, 2018.
- IARC Working Group on the Evaluation of Carcinogenic Risks to Humans: Human papillomaviruses. IARC Monogr Eval Carcinog Risks Hum 100 (Pt B), 255-313, 2012. Available online. Last accessed February 1, 2018.
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