Summary
Cervical cancer is the third most common type of cancer amongst US women. 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.
Epidemiology
-
Incidence of gynecological malignancies in the United States
- Endometrial
- Ovarian
- Cervical
-
Mortality rate due to gynecological malignancies in the United States
- Ovarian
- Cervical
- Endometrial
- Mean age at diagnosis: 48 years
- Highest incidence and mortality rates in African-American and Hispanic women
References:[1][2]
Epidemiological data refers to the US, unless otherwise specified.
Etiology
Almost all malignant lesions of the cervix are preceded by HPV infection.
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Infection with high-risk HPV types: 16 ;, 18
- Production of oncoproteins
- E6 → inhibiton of p53 protein → inhibition of intrinsic apoptotic pathway and inhibition of p21
-
E7 →
- Inhibiton of retinoblastoma protein → increased activity of E2F-family of transcription factors
- Inhibits p21 and p27 (CDK inhibitors) → increased activity of cyclin-dependent kinase
- Production of oncoproteins
-
Risk factors
- 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.
References:[3][3][4][5]
Clinical features
Patients are usually asymptomatic in early stages. Symptoms commonly first appear in advanced disease.
- 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
- 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!
References:[3][6][7]
Diagnostics
Pap smear (cervical smear)
The proper technique is essential for obtaining highly specific test results.
- The specimen is collected using a spatula or brush:
- Scraping of ectocervix
- Scraping of endocervix
- 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 Bethesda system
Bethesda system
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 of undetermined significance |
| |
Atypical squamous cells (cannot exclude HSIL) | ||
Low-grade squamous intraepithelial lesion |
| |
Atypical glandular cells | AGC |
|
High-grade squamous intraepithelial lesion |
|
Immediate conization of ASC-H and CIN-I lesions is no longer recommended!
Cervical intraepithelial neoplasia (CIN) classification
CIN, noninvasive disease, is a precursor of invasive cervical cancer. Evaluation of cervical cytology (via Pap smear or cervical biopsy) is used to classify CIN lesions.
Cervical intraepithelial neoplasia | Histology | Corresponding Bethesda classification |
---|---|---|
CIN I |
| |
CIN II |
| |
CIN III |
| HSIL |
Cervical intraepithelial neoplasia (CIN) typically occurs in young adults (25–35 years)!
HPV testing
- Indications: women > 30 years of age
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Procedures
- PCR: detection of HPV DNA
- Histology: presence of koilocytes
- Prolonged screening interval: screening every 5 years with HPV co-test (Pap smear + HPV test) instead of every 3 years with Pap smear alone
Pap smear testing and HPV testing (co-testing) are routine once patients reach the age of 30!
Colposcopy
- Allows for closer visualization of lesions and directed biopsies
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Cervical leukoplakia: atypical cells that form a white membrane that cannot be scraped off
- May indicate hyperkeratosis, parakeratosis, or cervical intraepithelial neoplasia
- Leukoplakia can arise at or near the transformation zone
- Further evaluation → biopsy
Conization
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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
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Cone biopsy must include the transformation zone as it is the most common site for CIN:
- Premenopausal: transformation zone located on ectocervix → shallow cone
- Postmenopausal: transformation zone located on endocervix → deep cone
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Complications
- Intraoperative or postoperative bleeding
- Cervical stenosis causing infertility
- Cervical insufficiency during pregnancy
- Infection, uterine perforation
References:[3][8][9][10][11][12][13][14][15][16][17][18][19]
Pathology
Cervical carcinoma most commonly arises from metaplastic squamous cell epithelium in the transformation zone.
-
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)
- Subtypes include mucinous, endometrioid, clear cell, and serous adenocarcinoma; . The most common is the endocervical mucinous subtype.
- Histology: atypical columnar epithelium with elongated nuclei
References:[20][21]
Treatment
Treatment depends on whether disease is invasive or noninvasive.
Noninvasive disease
Cervical intraepithelial neoplasia | Management | Definitive treatment | Follow-up |
---|---|---|---|
CIN I |
|
| |
CIN II |
| ||
CIN III |
|
Invasive disease
- 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 | |||||
Identified only by microscopy (and width < 7 mm) | Depth ≤ 3 mm |
|
| |||
Depth > 3 mm and < 5 mm |
| |||||
Clinical lesions confined to cervix or lesions greater than IA | Clinical lesion of < 4 cm in size | |||||
Clinical lesion of > 4 cm in size |
|
| ||||
Involvement of the upper two-thirds of the vagina, without parametrial invasion | Clinically visible lesion ≤ 4 cm | |||||
Clinically visible lesion > 4 cm | ||||||
Parametrial invasion but not onto pelvic sidewall | ||||||
Involvement of lower third of vagina | ||||||
Invasion of pelvic sidewall or hydronephrosis | ||||||
Spread to adjacent organs | ||||||
Spread to distant organs |
|
| ||||
Legend | ||||||
* 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:
|
References:[3][14][22][23][24][25][26][27]
Complications
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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
- Cancer anorexia-cachexia syndrome (CACS)
- Complications of radiation therapy
References:[28][29]
We list the most important complications. The selection is not exhaustive.
Prognosis
- Patients without lymph node involvement (N0) have a very good prognosis
- Onset of disease at a young age is associated with a poorer prognosis
- Death most often occurs secondary to bilateral ureteral obstruction (subsequent uremia).
References:[3]
Prevention
Primary prevention
Preventing primary infection with HPV with HPV immunization preferably before first sexual intercourse.
-
Indications
-
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
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Current guidelines: [30][31]
-
Administration of 2 doses of nine-valent HPV vaccine to all individuals between 11–12 years of age
- The 2nd dose should be administered 6–12 months after the 1st dose.
- Immunization can be started as early as 9 years of age.
-
Administration of 3 doses of nine-valent HPV vaccine to all unvaccinated individuals between 15–26 years of age.
- The 2nd dose should be given 1–2 months after the 1st dose and the 3rd dose 6 months after the first dose.
- Also preferred regimen for vaccination of immunocompromised individuals (e.g., HIV) [32]
-
Administration of 2 doses of nine-valent HPV vaccine to all individuals between 11–12 years of age
-
Previous guidelines
-
FDA-approved vaccines
- 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)
- Nine-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
Secondary prevention
Every woman aged 21–65 should undergo screening for cervical cancer.
The ACOG currently recommends the following screening for women with previously normal exams:
- < 21 years: no screening required
- 21–29 years: Pap smear every 3 years
- 30–65 years: Pap smear every 3 years OR co-testing (Pap smear with HPV test) every 5 years
-
> 65 years: no more testing required if the previous testing was negative
- Immunocompromised women (e.g., HIV) and women with DES exposure but average life-expectancy should continue screening
- Screening for women with HIV: Pap smear twice in the first year after HIV diagnosis and annually thereafter
References:[33][34][35]
Special patient groups
Pregnancy
- 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: Diagnostic conization; vaginal or cesarian delivery possible
- If margins are not clear → cesarian delivery and repeat conization postpartum
- No microscopic tumor: simple trachelectomy or neoadjuvant chemotherapy depending on tumor size
-
FIGO IA: Diagnostic conization; vaginal or cesarian delivery possible
-
Late pregnancy
- FIGO IA-IB1: Treatment may be postponed until after delivery.
- Advanced cancer: neoadjuvant chemotherapy or termination of pregnancy
-
Early pregnancy
Avoid loop electrosurgical excision in pregnant patients!
References:[36]