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Cervical Cancer for ABIM

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Cervical Cancer for the American Board of Internal Medicine Exam
Definition and Epidemiology
  • Definition
    • Cervical cancer originates from the cervix, most commonly in the transformation zone where the squamous and columnar epithelia meet.
    • The two primary histologic types are squamous cell carcinoma (about 80% of cases) and adenocarcinoma (about 15%).
  • Epidemiology
    • Cervical cancer is the fourth most common cancer in women worldwide.
    • Incidence rates are highest in low- and middle-income countries due to limited access to screening and preventive care.
    • HPV vaccination and regular screening programs have reduced incidence in developed countries.
Risk Factors
  • Human Papillomavirus (HPV) Infection:
    • HPV, particularly types 16 and 18, is the leading cause of cervical cancer.
    • Persistent infection with high-risk HPV strains is associated with cervical dysplasia and subsequent cancer.
  • Sexual Activity:
    • Early onset of sexual activity, multiple sexual partners, and a partner with a high number of sexual contacts increase the risk of HPV exposure.
  • Smoking:
    • Cigarette smoking has been linked to increased cervical cancer risk, likely due to immunosuppression and carcinogenic metabolites found in cervical mucus.
  • Immunosuppression:
    • Conditions like HIV/AIDS and immunosuppressive medications increase susceptibility to HPV infections and accelerate progression from dysplasia to cancer.
  • Long-Term Oral Contraceptive Use:
    • Prolonged use of oral contraceptives (≥5 years) has been associated with a slightly elevated risk of cervical cancer, though the risk decreases after discontinuation.
Pathophysiology
  • HPV-Induced Transformation:
    • High-risk HPV strains produce oncoproteins E6 and E7, which inactivate tumor suppressor proteins p53 and Rb, leading to uncontrolled cell division and progression from dysplasia to carcinoma.
  • Cervical Intraepithelial Neoplasia (CIN):
    • HPV infection can cause a spectrum of premalignant lesions classified as CIN 1 (mild dysplasia), CIN 2 (moderate dysplasia), and CIN 3 (severe dysplasia or carcinoma in situ).
    • CIN 1 often regresses spontaneously, while CIN 2 and 3 have a higher risk of progressing to invasive carcinoma, particularly in immunosuppressed individuals.
Clinical Manifestations
  • Early-Stage Disease:
    • Often asymptomatic, especially in preinvasive and early invasive stages.
    • Abnormal findings may be identified incidentally on routine Pap smears.
  • Advanced Disease:
    • Common symptoms include abnormal vaginal bleeding (postcoital, intermenstrual, or postmenopausal), pelvic pain, and increased vaginal discharge.
    • In advanced stages, symptoms may involve bladder or rectal invasion, leading to urinary symptoms, constipation, or hematochezia.
Diagnosis
  • Screening Tests:
    • Pap Smear (Cytology): Cytologic examination of cervical cells is the primary screening tool, recommended every 3 years for women aged 21-29, and co-testing (Pap smear + HPV test) every 5 years from ages 30-65.
    • HPV Testing: Co-testing with HPV DNA testing improves sensitivity for detecting high-risk HPV strains.
Cervical Cancer Cells
  • Colposcopy:
    • Indicated for abnormal Pap smear results, particularly for high-grade lesions (e.g., HSIL).
    • Colposcopy involves using a magnified view of the cervix with acetic acid application to identify abnormal epithelium.
  • Biopsy:
    • Directed cervical biopsy during colposcopy allows histopathologic evaluation to confirm CIN or invasive carcinoma.
  • Imaging:
    • MRI and CT: Used to assess the extent of disease in advanced cases, especially for detecting parametrial invasion or lymph node involvement.
    • PET-CT: Useful for identifying distant metastasis and guiding staging.
Staging
  • FIGO Staging System:
    • Stage I: Confined to the cervix.
    • Stage II: Extension beyond the cervix but not to the pelvic wall or lower third of the vagina.
    • Stage III: Invasion to the pelvic wall, lower third of the vagina, or causing hydronephrosis.
    • Stage IV: Spread to adjacent organs or distant metastasis (e.g., bladder, rectum, lungs).
Treatment
  • Early-Stage Disease (Stage IA1 to IB1):
    • Conization or Simple Hysterectomy: For microinvasive disease, particularly in women desiring fertility preservation.
    • Radical Hysterectomy with Pelvic Lymphadenectomy: Recommended for invasive lesions without parametrial involvement.
  • Locally Advanced Disease (Stage IB2 to IVA):
    • Radiation Therapy with Concurrent Chemotherapy: Standard treatment, typically with cisplatin-based chemotherapy, for tumors extending beyond the cervix.
    • Brachytherapy: Intracavitary radiation therapy is often combined with external beam radiation for improved local control.
  • Advanced or Metastatic Disease (Stage IVB):
    • Systemic Chemotherapy: Palliative approach using agents such as cisplatin, paclitaxel, and bevacizumab.
    • Targeted Therapies: Bevacizumab, a VEGF inhibitor, has shown benefit when combined with chemotherapy in metastatic disease.
Prevention
  • HPV Vaccination:
    • Routine vaccination is recommended for boys and girls aged 11-12, with catch-up vaccinations for those up to age 26.
    • HPV vaccines (e.g., Gardasil 9) cover multiple high-risk HPV types, including 16 and 18, significantly reducing cervical cancer risk.
  • Screening:
    • Regular Pap smears and HPV testing have been effective in reducing cervical cancer incidence and mortality.
    • Screening guidelines recommend beginning Pap smears at age 21 and HPV co-testing from age 30 to 65, adjusting intervals based on risk factors and prior screening results.
Complications
  • Local Spread and Metastasis:
    • Cervical cancer can spread locally to the bladder, rectum, and surrounding pelvic structures.
    • Distant metastasis may involve the lungs, liver, and bones, particularly in advanced stages.
  • Treatment-Related Complications:
    • Surgical Risks: Includes bleeding, infection, and damage to surrounding organs.
    • Radiation Side Effects: Can lead to radiation cystitis, proctitis, and fibrosis, impacting bladder and bowel function.
    • Chemotherapy Toxicities: Potential for nephrotoxicity, neuropathy, and bone marrow suppression.
Prognosis
  • Prognostic Factors:
    • Dependent on stage at diagnosis, tumor size, lymph node involvement, and histologic type.
    • Early-stage disease has a favorable prognosis with a 5-year survival rate of over 90%, while advanced disease has a poorer outcome.
  • Recurrence:
    • Recurrent disease can occur locally or at distant sites and is more common in advanced-stage cancer at initial diagnosis.
Key Points
  • Cervical Cancer is predominantly caused by high-risk HPV types (16 and 18) and is the fourth most common cancer in women worldwide.
  • Risk Factors include HPV infection, smoking, immunosuppression, and prolonged oral contraceptive use.
  • Screening and Prevention:
    • Routine Pap smear and HPV testing reduce incidence, with guidelines recommending screening from ages 21-65.
    • HPV vaccination is effective in preventing high-risk HPV infections and reducing cervical cancer risk.
  • Symptoms: Early disease is often asymptomatic, while advanced disease presents with abnormal vaginal bleeding, pelvic pain, and possible urinary or bowel symptoms.
  • Diagnosis relies on Pap smears, colposcopy with biopsy, and imaging studies for staging.
  • Treatment:
    • Early-stage disease can be managed with conization or hysterectomy.
    • Locally advanced disease requires chemoradiation, and metastatic disease is treated with systemic chemotherapy and targeted therapy.
  • Complications include local invasion, metastasis, and treatment-related side effects (e.g., radiation cystitis, chemotherapy toxicities).
  • Prognosis is favorable in early-stage disease, with declining survival rates as cancer progresses to more advanced stages.

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