> Table of Contents > Cervical Malignancy
Cervical Malignancy
Benjamin P. Brown, MD
Meaghan Tenney, MD
image BASICS
DESCRIPTION
  • Invasive cancer of the uterine cervix
  • Commonly involves the vagina, parametria, and pelvic side walls
  • Invasion of bladder, rectum, and other pelvic sites in advanced disease
EPIDEMIOLOGY
Incidence
  • In the United States, cervical cancer is the third most common gynecologic malignancy.
  • It is the second most common cancer among women in the developing world, with these patients representing >80% of reported cases.
  • The disease has a bimodal distribution, with the highest risk among women aged 40 to 59 years and >70 years.
Prevalence
  • In 2015, the American Cancer Society (ACS) estimated there were 12,900 new cases in the United States, with 4,100 deaths from the malignancy.
  • African Americans and women in lower socioeconomic groups have the highest cervical cancer death rates.
  • Hispanic and Latina women have the highest incidence of the malignancy.
ETIOLOGY AND PATHOPHYSIOLOGY
  • Arises from preexisting dysplastic lesions, usually following persistent human papillomavirus (HPV) infection
  • May be exophytic or endophytic
  • Lymphatic spread
  • Local tumor extension involving the bladder, ureters, rectum, and distant metastasis from hematogenous spread (Halstedian growth)
  • Epidemiologic and experimental evidence supports HPV strains 16 and 18 as etiologic agents in ˜70% of cervical cancers.
  • Association with E6 and E7 oncogenic proteins responsible for malignant cell transformation by inactivation of p53 and Rb tumor suppressor genes
  • Slow progression from dysplasia to invasive cancer allows time for screening and treatment of preinvasive disease.
Genetics
Not an inherited disease, except in very rare cases of Peutz-Jeghers syndrome
RISK FACTORS
  • Causative agent in the majority of cases is persistent HPV infection.
  • Other risk factors include the following:
    • Lack of regular Pap smears
    • Early coitarche
    • Multiple sexual partners
    • Unprotected sex
    • A history of sexually transmitted diseases (STDs)
    • Low socioeconomic status
    • High parity
    • Cigarette smoking
    • Immunosuppression
    • Diethylstilbestrol (DES) exposure in utero
GENERAL PREVENTION
  • Patient education regarding safer sex
  • Smoking cessation
  • HPV vaccines
    • Gardasil vaccines: quadrivalent and 9-valent options; FDA approved in females and in males (for prevention of genital warts and anal cancer)
    • Cervarix vaccine: bivalent vaccine against oncogenic HPV strains 16 and 18
    • No vaccine yet conclusively shown to prevent cancer
    • Recommended age of vaccination is 11 to 12 years (prior to coitarche), but Gardasil is approved from 9 to 26 years and Cervarix from 10 to 25 years.
  • Regular Pap smears and pelvic exams at appropriate intervals. In patients with no history of abnormal Paps, current guidelines from the American College of Obstetricians and Gynecologists (ACOG) are as follows:
    • Cytology alone every 3 years between 21 and 30 years
    • Cytology plus HPV testing every 5 years after 30 years (1)[C]
  • The International Federation of Gynecology and Obstetrics (FIGO) recommends visual inspection with acetic acid (VIA) or Lugol's iodine (VILI) as alternatives to Pap smears in resource-poor settings (2)[C].
  • Despite HPV vaccination, cervical cancer screening will remain the main preventive measure for both vaccinated and nonvaccinated women.
COMMONLY ASSOCIATED CONDITIONS
  • Condyloma acuminata
  • Preinvasive/invasive lesions of the vulva and vagina
image DIAGNOSIS
PHYSICAL EXAM
  • Disease is staged clinically, not surgically.
  • 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.
    • May have watery, purulent, or bloody discharge
  • Bimanual and rectovaginal examination for uterine size, vaginal wall, rectovaginal septum, 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
  • Marked cervicitis and erosion
  • Glandular hyperplasia
  • Sexually transmitted infection
  • Cervical condyloma, leiomyoma, or polyp
  • Metastasis from endometrial carcinoma or gestational trophoblastic neoplasia
DIAGNOSTIC TESTS & INTERPRETATION
Initial Tests (lab, imaging)
  • Biopsy of gross lesions and colposcopically directed biopsies are the definitive means of diagnosis.
  • CBC may show anemia.
  • Urinalysis may show hematuria.
  • In advanced disease, BUN, creatinine, and liver function tests (LFTs) may be helpful.
  • CT scan of the chest, abdomen, and pelvis and/or a positron emission tomography (PET) scan
  • Apart from chest x-ray (CXR) and intravenous pyelogram (IVP), imaging does not alter tumor stage.
  • MRI may be helpful in evaluating parametrial involvement in patients who are surgical candidates or for radiation treatment planning.
Follow-Up Tests & Special Consideration
Prompt multidisciplinary plan of care
  • Exam under anesthesia may help in determining clinical stage and disease extent and determine if patient is a surgical candidate.
  • Endocervical curettage and cervical conization as indicated to determine depth of invasion and presence of lymphovascular involvement
  • Cystoscopy to evaluate bladder invasion
  • Proctoscopy for invasion into rectum
Test Interpretation
  • Majority of cases (80%) are invasive squamous cell types usually arising from the ectocervix.
  • Adenocarcinomas comprise 10-15% of cervical cancer arising from endocervical mucus-producing glandular cells. Often, no exophytic lesion but a “bulky” “barrel-shaped” cervix present on exam.
  • Other cell types that may be present include rare mixed cell types, neuroendocrine tumors, sarcomas, lymphomas, and melanomas.
image TREATMENT
GENERAL MEASURES
Improve nutritional state, correct any anemia, and treat any vaginal and/or pelvic infections.
MEDICATION
  • Chemoradiation with cisplatin-containing regimen has superior survival rates over pelvic and extended-field radiation alone (3)[A].
  • Neoadjuvant chemotherapy may improve survival for early and locally advanced tumors, but more data are needed (4)[A].
  • Adjuvant chemotherapy after chemoradiation may improve progression-free survival in patients who receive primary chemoradiation for stages IIB-IVA tumors. The OUTBACK trial will further investigate these findings (http://www.clinicaltrials.gov).
  • P.181

  • The addition of bevacizumab to standard combination chemotherapy (cisplatin/topotecan or cisplatin/paclitaxel) for recurrent, persistent, or metastatic disease has been shown to improve overall survival (5)[A].
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 IIB and higher (gross lesions with obvious parametrial involvement) and for most bulky stage IB2 tumors (6)[A].
  • 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
  • Surgical management is an option for patients with early-stage tumors.
  • Removal of precursor lesions (cervical intraepithelial neoplasia [CIN]) by loop electrosurgical excision procedure (LEEP), cold knife conization, laser ablation, or cryotherapy
  • Stage IA1 (lesions with <3-mm invasion from basement membrane) without lymphovascular space invasion: option of conization or simple extrafascial hysterectomy (6)[A]
  • Stage IA2 (lesions with >3-mm but <5-mm invasion from basement membrane): option of radical hysterectomy with lymph node dissection or radiation, depending on clinical setting (6)[A]
  • Stages IA2-IB1: Fertility-sparing radical trachelectomy may be considered in selected patients (6)[A].
  • Stages IB1-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 (6)[A]
  • Stage IVA (lesions limited to central metastasis to the bladder and/or rectum): Primary pelvic exenteration may be feasible (6)[A].
  • Stage IVB disease is treated with goal of palliation. Early referral to palliative care should be made (6)[A],(7)[C].
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.
  • CIN1 or less: postpartum follow-up
  • CIN2-3: management per established guidelines
  • Microinvasive carcinoma: conization or trachelectomy. If depth of invasion ≤3 mm, follow up at the 6-week postpartum visit
  • Invasive carcinoma: definitive therapy, with timing determined by maternal preference, stage of disease, and gestational age
INPATIENT CONSIDERATIONS
Admission Criteria/Initial Stabilization
  • Signs of active bleeding
  • Urinary symptoms
  • Dehydration
  • Complications from surgery, chemotherapy, or radiation
  • Active vaginal bleeding can be controlled with timely vaginal packing and radiation therapy.
  • Recognition of ureteral blockage, hydronephrosis, urosepsis, and timely intervention
Discharge Criteria
Discharge criteria based on multidisciplinary assessment
image ONGOING CARE
FOLLOW-UP RECOMMENDATIONS
Patient Monitoring
  • With completion of definitive therapy and based on individual risk factors, patients are evaluated with physical/pelvic examinations:
    • Every 3 to 6 months for 2 years
    • Every 6 to 12 months until the 5th year
    • Yearly thereafter (8)[C]
  • Pap smears may be performed yearly but have a low sensitivity for detecting recurrence (8)[C].
  • CT and PET scan are useful in locating metastases when recurrence is suspected (8)[C].
  • Signs of recurrence include vaginal bleeding, unexplained weight loss, leg edema, and pelvic or thigh pain.
PATIENT EDUCATION
Patient education material available through the ACOG at http://www.acog.org, the Society of Gynecologic Oncology at http://www.sgo.org, the Foundation for Women's Cancer at http://www.foundationforwomenscancer.org, the American Cancer Society at http://www.cancer.org, and the National Cancer Institute at http://www.cancer.gov.
PROGNOSIS

Stage

5-y Survival (%)

1

76-98

2

66-73

3

40-42

4

9-22

REFERENCES
1. Committee on Practice Bulletins—Gynecology. ACOG Practice Bulletin Number 131: screening for cervical cancer. Obstet Gynecol. 2012;120(5):1222-1238.
2. International Federation of Obstetrics and Gynecology. Global guidance for cervical cancer prevention and control. http://www.rho.org/files/FIGO_cervical_cancer_guidelines_2009.pdf.
3. Chemoradiotherapy for Cervical Cancer Metaanalysis Collaboration. Reducing uncertainties about the effects of chemoradiotherapy for cervical cancer: individual patient data meta-analysis. Cochrane Database Syst Rev. 2010;(1):CD008285.
4. Rydzewska L, Tierney J, Vale CL, et al. Neoadjuvant chemotherapy plus surgery versus surgery for cervical cancer. Cochrane Database Syst Rev. 2012;(12):CD007406.
5. Tewari KS, Sill MW, Long HJ III, et al. Improved survival with bevacizumab in advanced cervical cancer. N Engl J Med. 2014;370(8):734-743.
6. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: cervical cancer. http://www.nccn.org/professionals/physician_gls/pdf/cervical.pdf.
7. Smith TJ, Temin S, Alesi ER, et al. American Society of Clinical Oncology provisional clinical opinion: the integration of palliative care into standard oncology care. J Clin Oncol. 2012;30(8):880-887.
8. Salani R, Backes FJ, Fung MF, et al. Posttreatment surveillance and diagnosis of recurrence in women with gynecologic malignancies: Society of Gynecologic Oncologists recommendations. Am J Obstet Gynecol. 2011;204(6):466-478.
Additional Reading
  • American Society for Colposcopy and Cervical Pathology. Algorithms: updated consensus guidelines for managing abnormal cervical cancer screening tests and cancer precursors. http://www.asccp.org/Portals/9/docs/ASCCP%20Management%20Guidelines_August%202014.pdf.
  • Martin-Hirsch PP, Paraskevaidis E, Bryant A, et al. Surgery for cervical intraepithelial neoplasia. Cochrane Database Syst Rev. 2013;(12):CD001318.
  • Scarinci IC, Garcia FA, Kobetz E, et al. Cervical cancer prevention: new tools and old barriers. Cancer. 2010;116(11):2531-2542.
See Also
Abnormal Pap and Cervical Dysplasia
Codes
ICD10
  • C53.9 Malignant neoplasm of cervix uteri, unspecified
  • C53.0 Malignant neoplasm of endocervix
  • C53.1 Malignant neoplasm of exocervix
Clinical Pearls
  • Cervical cancer is the third most common gynecologic malignancy in the United States. Improving access to screening is likely to have the greatest impact in reduction of burden of disease.
  • Women with cervical cancer may be asymptomatic and have a normal physical exam.
  • Surgical management is an option for patients with early-stage tumors.
  • Chemoradiation is the first-line therapy for higher stage tumors.