Harvey's Garden

Cervical cancer

4 min read

Epidemiology

Etiology

Risk factors

  • For contracting HPV infection
    • Actions that increase the likelihood of HPV infection (strongest risk factor)
      • Multiple sexual partners
      • Lack of barrier contraceptive
    • Early-onset of sexual activity
    • Multiparity
    • Immunosuppression (e.g., HIV infection, post-transplantation)
  • Environmental risk factors
    • Cigarette smoking and/or exposure to second-hand smoke (for squamous cell cancer types only)
    • In-utero exposure to diethylstilbestrol (DES)

Pathophysiology

Overview of terminology

Two-tiered terminology (Bethesda system)

  • High-grade squamous intraepithelial lesion (HSIL)
    • Lesions with moderate to severe epithelial dysplasia that are most likely associated with persistent HPV infection
    • HSIL lesions can progress to invasive cervical cancer (precancerous lesion).
  • Low-grade squamous intraepithelial lesion (LSIL)
    • Lesions with mild epithelial dysplasia that are typically associated with transient HPV infections
    • Correlates with CIN1

Three-tiered terminology

  • Cervical intraepithelial neoplasia (CIN) is characterized by epithelial dysplasia that begins at the basal layer of the squamocolumnar junction and extends outward.
  • Based on the degree of dysplasia, lesions are classified as CIN1 (mild), CIN2 (moderate), or CIN3 (severe).

Current standard

The current standard for reporting cervical histopathology and cytopathology to ensure optimal management is a combination of the two-tier and three-tier system (i.e., the two-tiered nomenclature with an additional qualifier using the intraepithelial neoplasia nomenclature).

  • LSIL correlates with CIN1.
  • HSIL correlates with CIN3 and CIN2.
  • HSIL should be specified as HSIL (CIN2), HSIL (CIN3), or HSIL unspecified.

Normal cervix

  1. Endocervix: inner part of the cervix proximal to the uterine external os
    • Composed of simple columnar epithelium with mucous-producing cells
  2. Cervical transformation zone: physiologic transition zone between the endocervix and ectocervix
    • Exact location is variable
    • Site of the squamocolumnar junction: the border between metaplastic squamous epithelium and simple columnar epithelium
    • Cervical cancer most commonly occurs in this zone.
  3. Ectocervix: outer part of the cervix distal to the uterine external os
    • Composed of stratified squamous epithelium (nonkeratinized)

Clinical features

Diagnostics

Differential diagnostics

FeatureCervical CancerEndometrial Cancer
PathophysiologyHPV 16, 18 (E6 inhibits p53, E7 inhibits Rb). Arises at the transformation zone.Unopposed estrogen leads to endometrial hyperplasia.
Classic PatientYounger, multiple sexual partners, smoker, immunosuppressed (HIV).Older, obese, nulliparous, diabetic. Postmenopausal.
Key PresentationPostcoital bleeding. Often asymptomatic until advanced.Postmenopausal bleeding.
ScreeningPap test +/- HPV co-testing.None for asymptomatic women.
DiagnosisColposcopy with directed biopsy.Endometrial biopsy. TVUS shows thickened stripe (>4mm).
HistologySquamous Cell Carcinoma (most common).Endometrioid adenocarcinoma (most common).
Major Risk Factors- Multiple sexual partners
- Immunosuppression
- Smoking		- Obesity
- Nulliparity
- Unopposed estrogen therapy
- Tamoxifen
Primary TreatmentHysterectomy or chemoradiation (stage-dependent).Total Hysterectomy + BSO.
PreventionHPV vaccine.Progestins (in combined OCPs/HRT), weight control.

Pathology

  • Invasive cervical carcinoma is characterized by invasion of the tumor beyond the basement membrane of the cervical epithelium.
  • HSIL and invasive cervical carcinoma most commonly arise from metaplastic squamous cell epithelium in the cervical transformation zone

Squamous cell carcinoma (∼ 80% of cases)

  • Subtypes include large cell keratinizing, large cell nonkeratinizing, and papillary squamous cell carcinoma.
  • Irregular cell morphology
  • Hyperchromatic cells with nonspherical nuclei, mitotic activity, and prominent nucleoli
  • Loss of basal membrane

Tip

  • Staging (Simplified FIGO)
    • Stage I: Confined strictly to the cervix.
    • Stage II: Invades beyond the uterus, but not to the pelvic wall or lower third of the vagina.
      • Stage IIB is clinically important as it involves parametrial invasion.
    • Stage III: Tumor extends to the pelvic wall, and/or involves the lower third of the vagina, and/or causes hydronephrosis.
    • Stage IV: Extends beyond the true pelvis or involves mucosa of bladder/rectum (IVA) or has distant metastases (IVB).

Treatment

Pre-Invasive (CIN / HSIL)

  • CIN 1: Observe (most regress).
  • CIN 2, 3 (HSIL): Excisional procedures are standard.
    • Loop Electrosurgical Excision Procedure (LEEP): Most common method.
      • An electrically heated wire loop removes the transformation zone and lesion. Provides a tissue specimen for histology to rule out invasive cancer.
    • Cold Knife Conization (CKC): If lesion extends into endocervical canal or for adenocarcinoma in situ (AIS).

Early-Stage Invasive Cancer (FIGO Stage IA - IIA1)

  • Stage IA1: Cone biopsy or simple hysterectomy.
  • Stage IA2 - IIA1 (< 4cm):
    • Option 1: Radical hysterectomy + pelvic lymph node dissection (LND).
    • Option 2: Primary chemoradiation (equally effective).
  • Fertility Sparing (select cases): Radical trachelectomy + LND.

Locally Advanced Cancer (FIGO Stage IB2 - IVA)

  • Standard of Care: Definitive chemoradiation.
    • External beam radiation (EBRT) + brachytherapy.
    • Concurrent cisplatin-based chemotherapy (radiosensitizer).
  • Surgery is NOT the primary treatment.
    • Due to high rates of positive margins and nodal metastasis.

Metastatic (Stage IVB) or Recurrent Disease

  • Goal: Palliative.
  • Treatment: Systemic therapy.
    • First Line: Carboplatin + Paclitaxel +/- Bevacizumab (anti-VEGF).
    • Immunotherapy: Add Pembrolizumab (anti-PD-1) for PD-L1 positive tumors.

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