Description

Cervical cancer is a malignant neoplasm arising from the cells of the uterine cervix. Most cervical cancers, almost 90%, are squamous cell carcinomas and begin in the squamocolumnar junction where the exocervix and endocervix meet, also known as the transformation zone. A small percentage of cervical cancers are adenocarcinomas and begin in the glandular cells of the endocervix.

Epidemiology

Etiology and Pathophysiology

• Human papillomavirus (HPV) infection with high-risk (HR) serotypes, especially HPV 16 and HPV 18, is the most important etiologic factor.
• HPV infection has high prevalence with most sexually active adults having it at one point in their lives.
• HR HPV accounts for 99% of all cervical cancer.

Risk Factors

• Persistent HPV infection is the primary risk factor for developing cervical cancer.
• Other risk factors include lack of or decreased access to health care and ability to obtain regular Pap tests; early coitarche especially before the age of 18; multiple sexual partners; unprotected sex; a history of sexually transmitted infections (STIs); low socioeconomic status; first birth prior to age of 2 years; high parity (≥3 full-term deliveries); cigarette smoking (doubles the risk); immunosuppression (HIV/AIDS, chemotherapy); diethylstilbestrol (DES) exposure in utero; oral contraceptive use of ≥5 years (risk back to baseline after ≥10 years of nonuse), family history of cervical cancer

General Prevention

• The cornerstone of prevention includes not only routine screening with a Pap test (or HPV test) but also vaccination against HR-HPV.
• The three FDA-approved vaccines are four-serotype Gardasil 4, nine-serotype Gardasil 9, and two-serotype (HPV 16 and 18) Cervarix, but only Gardasil 9 is currently distributed.
• Vaccination is recommended for:
  • Everyone through the age of 26
  • Girls and boys ages 11 or 12 years in 2 doses, 6 to 12 months apart. It can also be given as early as 9 years of age.
  • Children ≥15 years should receive 3 doses over the course of 6 months.
  • Immunocompromised patients ages 9 to 26 years, men who have sex with men, and the LGBTQ community
• Current guidelines from the US Preventive Services Task Force (USPSTF 2018), ASCCP (2021), and ACOG (2021) recommend screening as follows (2):
  • Women aged 21 to 29 years: cytology alone every 3 years
  • Women aged 30 to 65 years: cytology alone every 3 years, HR-HPV testing (using an assay specifically approved by the FDA for HPV-screening-only testing) alone every 5 years, or cytology plus HR-HPV cotesting every 5 years
• An alternative screening algorithm using a risk-based strategy and specific FDA-approved high-risk HPV tests followed by cytology for positive screens is a recommended alternative.
• Management of abnormal results obtained from screening should involve personalized risk assessment for the individual patient using ASCCP management guidelines (available via web-based and mobile applications) (2)

Commonly Associated Conditions

Condyloma acuminata, preinvasive/invasive lesions of the vulva, vagina, oral, anal, and oropharyngeal cancers

History

• Patients with HPV infection may be asymptomatic. Early stages can be discovered incidentally as a result of cervical cancer screening.
• The most common symptoms of cervical cancer are irregular or heavy bleeding, postcoital vaginal bleeding, unusual discharge, pain with sex, or pelvic pain.

Physical Exam

• A thorough pelvic exam is essential. Many patients have a normal exam, especially with microinvasive disease. Lesions may be exophytic, endophytic, polypoid, papillary, ulcerative, or necrotic.
• In women with symptoms of cervical cancer, bimanual and rectovaginal examination should be performed to evaluate uterine size, vaginal wall, rectovaginal septum, and parametrial, uterosacral, and pelvic sidewall involvement.
• Enlarged supraclavicular or inguinal lymphadenopathy, lower extremity edema, ascites, or decreased breath sounds with lung auscultation may indicate metastases or advanced stage disease.

Differential Diagnosis

• Cervical condyloma, leiomyoma, or polyp
• Metastasis from endometrial carcinoma or gestational trophoblastic neoplasia.

Diagnostic Tests & Interpretation

General Measures

Improve nutritional state, correct anemia (Hb <12 g/dL), and treat pelvic infections. Lymph node evaluation is key to staging and treatment. Correction of urinary tract obstruction is important prior to beginning chemoradiation. Pretreatment evaluation should be done prior to chemotherapy for lymph nodes involvement using PET/CT scan.

Medication

• Chemoradiation with a cisplatin-containing regimen is the preferred treatment for certain stages of cervical cancer
• Neoadjuvant chemotherapy may improve survival for early and locally advanced tumors. Adjuvant chemotherapy after chemoradiation may improve progression-free survival in patients who receive primary chemoradiation for stages IIB to IVA tumors.
• The addition of the antiangiogenesis drug bevacizumab to standard combination chemotherapy (cisplatin/topotecan or cisplatin/paclitaxel) for recurrent, persistent, or metastatic disease has been shown to improve overall survival.

Issues for Referral

Multidisciplinary management of patients as needed and in a timely fashion

Additional Therapies

• Chemoradiation (without surgery) is the first-line therapy for tumors stage IB3 and higher. Combination of external-beam pelvic radiation and brachytherapy is usually employed.
• If para-aortic lymph node metastases are suspected, extended-field radiation or lymph node dissection prior to radiation therapy may be performed.

Surgery/Other Procedures

• Removal of precursor lesions (cervical intraepithelial neoplasia [CIN]) by loop electrosurgical excision procedure (LEEP), cold knife conization, laser ablation, or cryotherapy
• Open hysterectomy is superior to laparoscopic hysterectomy for cervical cancer treatment for patients with stages IA1, IA1, and IB1.
• Stage IA2 (lesions with >3 mm but ≤5 mm depth): option of radical hysterectomy with lymph node dissection or radiation depending on clinical setting; robotic radical hysterectomy (RRH) has demonstrated to be superior to laparoscopic radical hysterectomy and open radical hysterectomy in intraoperative blood loss, length of hospital stay, and intraoperative and postoperative complications; RRH can be regarded as a safe and effective therapeutic procedure for the management of cervical cancer.
• Stages IA2 to IB1: Fertility-sparing radical trachelectomy may be considered in selected patients.
• Stages IB1 to IIA (gross lesions without obvious parametrial involvement): option of radical hysterectomy with lymph node sampling or primary chemoradiation with brachytherapy and teletherapy, depending on clinical setting (1); in stage IB, when comparing adjuvant radiotherapy with no adjuvant radiotherapy, there is no significant difference in survival at 5 years between women who received radiation and those who received no further treatment (risk ratio [RR] = 0.8, 95% confidence interval [CI] 0.3–2.4). However, women who received radiation had a significantly lower risk of disease progression at 5 years (RR 0.6, 95% CI 0.4–0.9).
• Stage IVA (lesions limited to central metastasis to the bladder and/or rectum): Primary pelvic exenteration may be feasible.
• Stage IVB (lesions spread to distant organs): Treatment goal is palliation; therefore, early referral to palliative care should be made.

Pregnancy Considerations

• Management is guided by consideration of stage of lesion, gestational age, and maternal assessment of risks and benefits from treatment. Abnormal cytology is best followed up by colposcopy with directed biopsies.
• In pregnant women with early stages (IA1, IA2, IB) diagnosed before 3 months’ gestation, treatment may be delayed to allow for fetal maturity.
• In pregnant women diagnosed with stage 1 cervical cancer in 2nd or 3rd trimester, a cold knife conization or radical trachelectomy may be suggested with plan for early C-section delivery.
• In pregnant women with advanced disease (stage 2 or higher) diagnosed in 2nd or 3rd trimester, chemotherapy may be recommended. Cisplatin, carboplatin, and paclitaxel usually do not harm the fetus if given in the second or third trimester but could possibly cause early labor or low-birth weight.

Admission, Inpatient, and Nursing Considerations

• Admission may be needed for active bleeding, dehydration, treatment complications, and ureteral blockage (with hydronephrosis or urosepsis).
• Active vaginal bleeding can be controlled with timely vaginal packing and radiation therapy.

Follow-up Recommendations

Patient Education

The Society of Gynecologic Oncology: https://www.sgo.org/; the Foundation for Women’s Cancer: https://foundationforwomenscancer.org/

Prognosis

• If detected early, invasive cervical cancer can be treated successfully. Survival rates were calculated based on women diagnosed with cervical cancer between the years of 2012 and 2018. Rates were calculated for each Surveillance, Epidemiology, and End Results (SEER) stage.
  • The 5-year survival rate for localized disease is estimated at 92%.
  • The 5-year survival rate for regional disease is estimated at 59%.
  • The 5-year survival rate for distant disease is estimated at 17%.
  • The 5-year survival rate for all SEER stages combined is estimated at 67%.
• An elevated squamous cell carcinoma antigen |(SCC-Ag) serum levels estimated by ELISA technique can be used to predict the clinical response to neoadjuvant chemotherapy and residual disease. Persistently elevated SCC-Ag level at 2 to 3 months after RT had a significantly higher incidence of treatment failure. Serum SCC-Ag levels are also useful for monitoring treatment efficacy, disease progression, recurrence, and poor prognosis in SCCs. The combination of clinical pelvic examination and SCC-Ag levels provides useful information for the further need of treatment.

Complications

• Loss of ovarian function from radiotherapy or indication for bilateral oophorectomy
• Hemorrhage, pelvic infection, genitourinary fistula, bladder dysfunction, sexual dysfunction
• Ureteral obstruction with renal failure, bowel obstruction, pulmonary embolism, lower extremity lymphedema

Additional Reading

Tewari KS, Monk BJ. Evidence-based treatment paradigms for management of invasive cervical carcinoma. J Clin Oncol. 2019;37(27):2472–2489.  [PMID:31403858]

See Also

Abnormal Pap and Cervical Dysplasia

ICD-10

• C53.9 Malignant neoplasm of cervix uteri, unspecified
• C53.0 Malignant neoplasm of endocervix
• C53.1 Malignant neoplasm of exocervix
• C53.8 Malignant neoplasm of overlapping sites of cervix uteri

SNOMED

• 363354003 Malignant tumor of cervix (disorder)
• 372097009 Malignant neoplasm of endocervix
• 372099007 Malignant neoplasm of exocervix