- Clinical science
Cervical cancer is the second most common type of cancer in women worldwide. In the United States, its incidence and mortality is well below that of breast, lung, endometrial, colon, and ovarian cancer. The mortality and incidence of cervical cancer have significantly declined after the introduction of routine Papanicolaou (Pap) smear screening. Cervical cancers are most often squamous cell carcinomas that arise from infection with a high-risk human papillomavirus (HPV) serotype. Consequently, the risk factors for cervical cancer are the same as those for HPV (e.g., early onset of sexual activity, multiple sexual partners, history of STDs, and immunosuppression). Growth of cervical carcinoma is preceded by cervical intraepithelial neoplasia (CIN), which can be detected via Pap smear. In the US, Pap smears are recommended for women between the ages of 21 and 64 and are subsidized for uninsured patients. Another method of prevention is vaccination against HPV. Currently, the HPV vaccine is recommended for individuals aged 9–45. Primary (i.e., vaccination) and secondary (i.e., screening) prevention are particularly important given that most patients are asymptomatic during early stages. Advanced cervical cancer typically presents with vaginal bleeding, pelvic pain, and/or lower back pain. Colposcopy, which allows for a cervical biopsy to be obtained, is a valuable diagnostic procedure. Lesions consisting of a high-grade CIN may be excised using conization. The treatment of invasive cervical cancer includes a combination of surgery, radiation therapy, and/or chemotherapy, depending on the stage of disease.
Incidence of gynecological malignancies in the United States
Mortality rate due to gynecological malignancies in the United States
- Mean age at diagnosis: 48 years
- Highest incidence and mortality rates in African-American and Hispanic women
Epidemiological data refers to the US, unless otherwise specified.
Infection with high-risk HPV types: 16 ;, 18 31, 33, 45, 51, 52, 56, 58
- Production of oncoproteins
- Early onset of sexual activity; multiple sexual partners (strongest risk factors)
- High parity
- Immunosuppression (e.g., HIV infection)
- History of sexually transmitted infections (e.g., herpes simplex, chlamydia)
- Cigarette smoking and/or exposure to second-hand smoke (for squamous cell cancer types only)
- Oral contraceptives
- Low socioeconomic status
- In-utero exposure to diethylstilbestrol (DES) has also been linked to cervical cancer, independently of HPV infection.
- Abnormal vaginal bleeding: menometrorrhagia, postcoital spotting, irregular vaginal bleeding
- Abnormal vaginal discharge: blood-stained or purulent malodorous discharge (not necessarily accompanied by pruritus)
- Cervical ulceration
Late symptoms: Tumor spread in this condition commonly occurs per continuitatem to the vagina, bladder, rectum and parametria.
- Hydronephrosis: obstructive nephropathy caused by compression of the ureters (FIGO III)
- Compression of veins or lymphatic vessels in the pelvic area, leading to swelling of the lower extremities
- Features of disseminated disease: lymphadenopathy or, rarely, abdominal, bone, or chest abnormalities (e.g., pain)
Always consider cervical cancer as a cause of postcoital bleeding!
The proper technique is essential for obtaining highly specific test results.
- The specimen is collected using a spatula or brush:
- A thin layer is uniformly applied to a glass slide.
- Immediate fixation using 95% ethyl alcohol (or spray fixative). Avoid air-drying!
- Stain with Papanicolaou dye
- Interpretation of cytologic smear according to the
The Bethesda system is used for classifying cytological results. Management guidelines exist for each determined subtype.
|Classification of cervical lesions according to cytology results||Abbreviation||Follow-up|
|Specimen unsatisfactory for evaluation|
|Negative for intraepithelial lesion or malignancy Including non-neoplastic cellular changes, inflammation, or glandular cell status posthysterectomy|| |
|Negative for intraepithelial lesion or malignancy but positive for high-risk HPV type|
|Atypical squamous cells (cannot exclude HSIL)|| |
|Low-grade squamous intraepithelial lesion|| |
|Atypical glandular cells||AGC|
|High-grade squamous intraepithelial lesion|
Cervical intraepithelial neoplasia (CIN) classification
|Cervical intraepithelial neoplasia||Histology||Corresponding Bethesda classification|
- Indications: women > 30 years of age
- Prolonged screening interval: screening every 5 years with HPV co-test (Pap smear + HPV test) instead of every 3 years with Pap smear alone
- Allows for closer visualization of lesions and directed biopsies
- Cervical leukoplakia: atypical cells that form a white membrane that cannot be scraped off
- Abnormal staining of the squamocolumnar junction
- Abnormal lesions
Procedure: excision of a cone of cervical tissue that contains parts of both the ectocervix and endocervix
- May be performed using a cold knife, electrosurgical loop (LEEP), or a laser
- Cone biopsy must include the transformation zone as it is the most common site for CIN:
- Local spread
- Imaging might not be useful for assessing local spread. However, if imaging is used, MRI is the best option.
- Abdominal/pelvic CT prior to radical hysterectomy (stages IA2 to IB1)
- PET/CT prior to chemoradiation therapy (stages IB2 to IVA)
- MRI or CT for urinary tract imaging. Intravenous pyelography (IVP) may be used if MRI or CT are not available.
Not to be used for screening purposes! Unfortunately, their value in monitoring cervical cancer has not yet been sufficiently studied.
- SCC in squamous cell carcinoma
- CEA or CA-125 in adenocarcinoma
Squamous cell carcinoma (∼ 80% of cases)
- Subtypes include (but are not limited to) large cell keratinizing, large cell nonkeratinizing, small cell, and papillary squamous cell carcinoma.
- Histology: irregular cell morphology; hyperchromatic cells with nonspherical nuclei, mitotic activity, and prominent nucleoli; loss of basal membrane
- Adenocarcinoma (∼ 20% of cases; increasing incidence)
Direct complications of cervical carcinoma
- Infiltration of ureter leading to urinary obstruction → hydronephrosis → kidney failure
- Fistula formation in locally advanced disease, e.g., rectovaginal, vesicovaginal, urethrovaginal
- Compression of veins or lymphatic vessels in the lesser pelvis, leading to congestion in the lower extremities
- CACS) (
Complications of radiation therapy
- Vaginal stenosis
- Radiogenic cystitis/proctitis
- Fistula formation
We list the most important complications. The selection is not exhaustive.
Treatment depends on whether disease is invasive or noninvasive.
|Cervical intraepithelial neoplasia||Management||Definitive treatment||Follow-up|
|CIN I|| || |
|CIN III|| |
- For microinvasive carcinoma
- Cone biopsy; and follow-up
- OR hysterectomy
- For advanced disease: First-line treatment is chemotherapy, radiation therapy, or a combination of both in patients with advanced disease, lymph node metastases, or who are poor surgical candidates.
|Anatomic location||Recommendations for therapy|
|Surgery||Radiation / Chemotherapy|
|I||IA||Identified only by microscopy (and width < 7 mm)||IA1||Depth ≤ 3 mm|| || |
Depth > 3 mm and < 5 mm
|IB||Clinical lesions confined to cervix or lesions greater than IA||IB1|| |
Clinical lesion of < 4 cm in size
Clinical lesion of > 4 cm in size
| || |
|II||IIA||Involvement of the upper two-thirds of the vagina, without parametrial invasion||IIA1||Clinically visible lesion ≤ 4 cm|
|IIA2||Clinically visible lesion > 4 cm|
|IIB||Parametrial invasion but not onto pelvic sidewall|
|III||IIIA||Involvement of lower third of vagina|
|IIIB||Invasion of pelvic sidewall or hydronephrosis|
|Spread to adjacent organs|
|Spread to distant organs|| |
* Risk features are based on histology and have been shown to have an impact on prognosis. They are taken into account when choosing the appropriate therapy. They include:
Preventing primary infection with HPV:
HPV immunization preferably before first sexual intercourse.
- Previous guidelines:
- Women 9–26 years of age and men 9–21 years of age
- Men who have sex with men: up to 26 years of age
Current guidelines: 
- 2 doses should be administered 6 months apart to all individuals between the ages of 11 and 12 years
- Immunization can be started as early as 9 years of age.
- 3 doses of nine-valent HPV vaccine should be administered for all unvaccinated individuals between the ages of 27 and 45 years.
- Previous guidelines:
- Bivalent vaccine (Cervarix®): protection against high-risk HPV types 16 and 18
- Tetravalent vaccine (Gardasil®): protection against high-risk HPV types 16 and 18, as well as against low-risk types 6 and 11 (most common cause of genital warts)
- 9-valent vaccine (Gardasil®9): protection against high-risk HPV types 16, 18, 31, 33, 45, 52, and 58, as well as against low-risk types 6 and 11
- Barrier protection (condoms) during sexual intercourse
- Sexual abstinence
Every woman aged 21–65 should participate in screening for cervical cancer.
- 21–29 years: Pap smear every 3 years
- 30–65 years: Pap smear every 3 years OR Pap smear + HPV test every 5 years
- > 65 years: no testing required if previous testing was negative
- Cervical cytology should be obtained from women during pregnancy.
- 1–3% of women suffering from cervical cancer are diagnosed during or shortly after their pregnancy.
- Management should take the patient's wishes into consideration and depends on the stage of pregnancy and disease.
- Early pregnancy
- FIGO IA-IB1: Treatment may be postponed until after delivery.
- Advanced cancer: neoadjuvant chemotherapy or termination of pregnancy
Avoid loop electrosurgical excision in pregnant patients!