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Carcinoma of the Cervix - A Comprehensive 30-Mark Answer

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Introduction

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Incidence and Epidemiology

• Accounts for ~6.6% of all female cancers globally; incidence is highest in Sub-Saharan Africa and South Asia.
• Peak incidence: 45-55 years for invasive cancer; precursor lesions (CIN) peak at ~30 years.
• In India, it is the most common gynecological cancer.

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Etiology and Risk Factors

Primary Cause: HPV

Risk Factors (mnemonic - SHEMP)

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Pathogenesis

HPV Oncogenesis (from Robbins Pathology)

1. HPV infects immature squamous cells in the transformation zone via micro-abrasions.
2. Viral E6 protein binds and degrades p53 (tumor suppressor) and upregulates telomerase.
3. Viral E7 protein binds retinoblastoma (Rb) protein, releasing E2F transcription factors, driving cell cycle progression.
4. High-risk HPV (16, 18) integrates into host genome - this disrupts the negative regulator of E6/E7, increasing their expression, and leads to genomic instability.
5. Low-risk HPV (6, 11) remains episomal - E7 binds Rb with low affinity; E6 does not bind p53.
6. Persistent infection + co-carcinogens --> CIN --> invasion.

Progression: CIN → Invasive Carcinoma

• LSIL (CIN I): HPV cytopathic effect (koilocytes); usually regresses
• HSIL (CIN II/III): Full-thickness dysplasia; higher risk of progression
• Invasive carcinoma: Breach of basement membrane
• SIL peaks at age 30; invasive cancer peaks at age 45 - suggesting a 10-15 year window for intervention

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Pathology

Histological Types

Squamous Cell Carcinoma Variants (Berek & Novak)

• Large cell keratinizing: Keratin pearls; best prognosis
• Large cell non-keratinizing: Individual cell keratinization; no pearls
• Small cell anaplastic: Resembles oat cell lung cancer; worst prognosis; diffuse infiltration

Spread

1. Direct: Parametrium, vagina, bladder, rectum
2. Lymphatic: Paracervical → obturator → internal/external iliac → common iliac → para-aortic nodes (most important route)
3. Hematogenous: Lungs, liver, bone (late, uncommon)

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Clinical Features

Symptoms

• Early: Asymptomatic (detected on screening); post-coital bleeding, intermenstrual bleeding, vaginal discharge (watery, then bloody, then offensive)
• Advanced: Continuous bleeding, pelvic pain, low back pain (sciatic involvement), urinary symptoms (frequency, hematuria, fistula), rectal bleeding, leg edema (lymphatic obstruction), weight loss, cachexia

Signs

• Cervix may appear normal (microinvasive), show an ectocervical erosion, exophytic cauliflower growth, ulcer, or barrel-shaped cervix
• Parametrial involvement felt on pelvic/rectal examination
• Nodal enlargement on abdominal examination

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Diagnosis and Investigations

1. Screening

• Pap smear (Papanicolaou): Mainstay of screening since mid-20th century; sensitivity ~51%, specificity ~98%
• Bethesda System classification: ASC-US, LSIL, HSIL, ASC-H, AGC, carcinoma
• HPV co-testing: Combined Pap + HPV DNA test; recommended from age 30 (ACOG)
• VIA (Visual Inspection with Acetic Acid): Low-cost alternative for low-resource settings; aceto-white lesions indicate CIN

2. Colposcopy

• Aceto-white epithelium, abnormal vascular patterns (punctation, mosaic, atypical vessels)
• Satisfactory colposcopy: squamo-columnar junction fully visible

3. Biopsy

• Punch biopsy: From colposcopically directed site
• Cone biopsy (conization): For microinvasive disease - diagnostic and potentially therapeutic for stage IA1

4. Staging Investigations (FIGO 2018 allows imaging)

• MRI pelvis: Gold standard for local tumor extent, parametrial invasion, vaginal involvement
• CT chest/abdomen/pelvis: Lymph node metastases, systemic spread
• PET-CT: Most sensitive for lymph node staging (especially para-aortic), recurrence
• Cystoscopy + rectosigmoidoscopy: For advanced disease (stages III-IV)
• IVP/renal ultrasound: Hydronephrosis in stage IIIB
• CXR: Pulmonary metastases
• Exam under anesthesia (EUA)
• Tumor markers: SCC antigen (squamous), CA 125 (adenocarcinoma) - monitoring treatment response

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Staging: FIGO 2018

Key rule: If doubt exists about a stage, assign the lower (earlier) stage. Once treatment begins, stage must not be changed.

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Treatment

Summary by Stage (Berek & Novak Table 38-4 concept)

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Surgical Treatment

Wertheim's Radical Hysterectomy (Type III)

• Includes: uterus + cervix + upper 1/3 vagina + parametrium + paracervical tissue + pelvic lymph nodes
• Indicated: Stages IA2, IB, IIA in medically fit patients
• Ovaries can be conserved (metastasis in only 0.9% of early disease)
• Advantages over radiotherapy: Preserves ovarian function, avoids radiation side effects, allows pathologic assessment of nodes

Wertheims Hysterectomy vs Radiotherapy

Minimally Invasive vs Open (Critical Update)

• Disease-free survival: MIS 86.0% vs Open 96.5% at 4.5 years
• Overall survival (3-year): MIS 91.2% vs Open 97.1%
• Possible cause: Uterine manipulator spreading malignant cells; CO2 insufflation
• Current recommendation: Open radical hysterectomy is preferred for cervical cancer.

Trachelectomy (Fertility-Sparing)

• Radical trachelectomy (cervical removal + pelvic nodes) with uterine preservation
• Indicated: Stage IA2 to IB1, tumor ≤2 cm, no lymph node involvement, desire for future fertility

Sentinel Lymph Node (SLN) Mapping

• Injection of blue dye/Tc-99m/ICG into cervix (3 and 9 o'clock)
• SLN most commonly at: medial to external iliac, ventral to hypogastric, superior obturator space
• NCCN recommends for tumors <2 cm

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Radiation Therapy

External Beam Radiotherapy (EBRT)

• Whole pelvis radiation (45-50 Gy in 25-28 fractions)
• Can sterilize pelvic lymph nodes and primary tumor

Brachytherapy (Intracavitary/Interstitial)

• Essential component for local tumor control
• LDR (Cs-137): Inpatient; 1-3 days continuous
• HDR (Ir-192): Outpatient; multiple fractions; modern standard
• Classic 2D: Point A (2 cm superior to external os + 2 cm lateral to canal) = 7,000-8,000 cGy
• Modern 3D image-guided brachytherapy (IGA-BT): MRI/CT-planned; 8,500-9,500 cGy to HR-CTV D90; reduces toxicity by half compared to 2D (French STIC trial)
• Dose limits: Bladder <90 Gy EQD2; Rectum/Sigmoid <75 Gy EQD2

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Concurrent Chemoradiation (CRT) - Standard for Locally Advanced Disease

• GOG Protocol 85: Cisplatin + 5-FU + RT vs hydroxyurea + RT - CRT showed significantly improved PFS and OS
• GOG Protocol 120: Weekly cisplatin arm showed superior results vs hydroxyurea; established weekly cisplatin as standard
• Intergroup trial (stages IA2-IIA with high-risk features post-surgery): Chemoradiation 4-yr survival 81% vs radiation alone 71%
• Current standard: Cisplatin-based concurrent chemoradiation for stages IIB-IVA and high-risk post-surgical patients

• Positive pelvic lymph nodes
• Positive parametrial margins
• Positive vaginal margins

• LVSI present + >1/3 stromal invasion + large tumor (Sedlis criteria)

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Prognosis by Stage

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Cervical Cancer in Pregnancy

• Most common gynecological cancer in pregnancy (1 in 1,000-10,000 pregnancies)
• Diagnosis: Colposcopy safe in pregnancy; biopsy if clinically suspicious
• Stage IA1: Delay treatment until delivery; cone biopsy if needed
• Stages IA2-IB1: Delay to fetal maturity (>34 weeks) acceptable; neoadjuvant cisplatin possible
• Advanced disease, early pregnancy: Immediate treatment with termination
• Mode of delivery: Caesarean section preferred to avoid seeding in birth canal; classical uterine incision

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Recurrent Cervical Cancer

• Central pelvic recurrence (post-radiation): Pelvic exenteration (total - bladder + uterus + rectum with stomas; anterior - bladder only; posterior - rectum only)
• Isolated lateral recurrence: Chemoradiation if not previously radiated
• Distant recurrence: Palliative systemic chemotherapy
• Chemotherapy regimens: Cisplatin + paclitaxel ± bevacizumab (anti-VEGF monoclonal antibody; GOG 240 trial showed survival benefit)

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Prevention

Primary Prevention - HPV Vaccination

• Best given before sexual debut (9-12 years, girls and boys)
• India's national program: Cervavac (quadrivalent, indigenously produced)
• WHO's 90-70-90 strategy: 90% girls vaccinated by 15; 70% of women screened by 35 and 45; 90% of women identified with disease treated

Secondary Prevention - Screening

• Cytology (Pap smear): Every 3 years from age 21-65
• Co-testing (Pap + HPV): Every 5 years from age 30-65
• Primary HPV testing: Emerging as preferred in many guidelines (2025 Canadian guidelines update - PMID: 41152983)
• VIA/VILI: For resource-limited settings

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Summary Flowchart for Exam

Cervical Cancer
├── Etiology: HPV 16/18 (70%) → E6 degrades p53, E7 inactivates Rb
├── Precursor: CIN I → II → III → Invasion (10-15 yr window)
├── Histology: SCC 75%, Adenocarcinoma 15-20%
├── Diagnosis: Pap smear → colposcopy → biopsy → staging
├── Staging: FIGO 2018 (allows imaging + pathology)
│   ├── IA: Microscopic (≤5 mm depth)
│   ├── IB: Clinically visible, confined to cervix (IB1 ≤2cm, IB2 2-4cm, IB3 >4cm)
│   ├── II: Beyond uterus (IIA = no parametrium; IIB = parametrium)
│   ├── III: Pelvic wall/lower vagina/hydronephrosis/LN (IIIC new in 2018)
│   └── IV: Bladder/rectum (IVA); distant (IVB)
├── Treatment
│   ├── Early (IA-IIA): Surgery (Wertheim's) OR chemoradiation - equivalent 5yr survival ~85%
│   ├── Advanced (IIB-IVA): Concurrent cisplatin chemoradiation + brachytherapy
│   └── Recurrence: Pelvic exenteration (central) / palliative CRT/chemo
└── Prevention: HPV vaccine + Pap/HPV screening

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