---

---

CARCINOMA CERVIX - Complete Exam Guide

---

1. EPIDEMIOLOGY

• 4th most common cancer in women worldwide; leading gynecologic cancer in developing countries.
• US incidence: ~12,578 new cases/year; ~4,115 deaths/year.
• Lifetime risk: 1 in 128 women.
• Mean age: 47 years; bimodal peaks at 35-39 years and 60-64 years.
• 30% of US cases occur in women who never had a Pap smear; in developing countries, this approaches 60%.
• Considered a preventable disease - long preinvasive state, effective screening, and treatable precursors.

---

2. ETIOLOGY AND PATHOGENESIS

Causal Agent: Human Papillomavirus (HPV)

• Detected in up to 99% of squamous cervical carcinomas.

• 100 HPV types; 15 are high-risk.

• HPV 16 and 18 found in up to 70% of cervical carcinomas.
• Mechanism of carcinogenesis:
  • E6 protein binds and degrades p53 → prevents apoptosis and cell cycle arrest at G1 checkpoint
  • E7 protein binds and inactivates Rb (retinoblastoma protein) → disrupts E2F transcription factor → unregulated cellular proliferation
  • Both steps are essential for malignant transformation.
• HPV causes both squamous cell carcinoma and adenocarcinoma (possibly via different carcinogenic pathways).

Cofactors

• Herpes simplex virus type 2 (HSV-2)
• Chlamydia trachomatis
• HIV (immune suppression) - cervical cancer is an AIDS-defining illness

Risk Factors

---

3. PATHOLOGY

A. Squamous Cell Carcinoma (~70-75%)

• Most common type. Arises from the transformation zone (squamocolumnar junction).
• Sequence: Normal epithelium → HPV infection → CIN 1 → CIN 2 → CIN 3/CIS → Invasive carcinoma.
• Subtypes: Large-cell keratinizing, large-cell non-keratinizing (most common), small cell, basaloid, papillary, warty.
• Verrucous carcinoma - rare, locally invasive, almost never metastasizes.

B. Adenocarcinoma (~20-25%)

• Arises from endocervical columnar epithelium.
• Incidence is increasing (both relative and absolute).
• Subtypes: Mucinous (most common), endometrioid, clear cell, serous.
• Minimal deviation adenocarcinoma (adenoma malignum) - associated with Peutz-Jeghers syndrome; deceptively bland histology.
• Less effectively detected by cytologic screening.
• Precursor: Adenocarcinoma in situ (AIS).

C. Adenosquamous Carcinoma

• Mixed glandular and squamous elements. More aggressive behavior.

D. Other Rare Types

• Neuroendocrine/small cell carcinoma - most aggressive; worst prognosis; treated like small cell lung cancer (cisplatin + etoposide)
• Glassy cell carcinoma - variant of poorly differentiated adenosquamous
• Lymphoepithelioma-like carcinoma - better prognosis
• Sarcoma, melanoma - rare

---

4. PATTERNS OF SPREAD

1. Direct extension:
   • Downward to vagina
   • Lateral to parametrium → pelvic sidewall
   • Anteriorly to bladder (vesicovaginal fistula)
   • Posteriorly to rectum (rectovaginal fistula)
   • Superiorly to uterine corpus
2. Lymphatic spread (most important clinical route):
   • Paracervical → Obturator → External iliac → Internal iliac → Common iliac → Para-aortic nodes
   • Also to presacral nodes
3. Hematogenous spread (late):
   • Lungs, liver, bone - uncommon in early disease

---

5. CLINICAL FEATURES

Symptoms

• Early: Often asymptomatic; abnormal Pap smear only finding
• Classic presenting symptom: Post-coital bleeding
• Intermenstrual or postmenopausal bleeding
• Vaginal discharge - watery, serous, or blood-stained; malodorous with necrosis
• Pelvic/back pain (advanced disease - suggests pelvic sidewall or nerve involvement)
• Advanced: Hematuria, rectal bleeding (vesical/rectal invasion), lower limb edema (lymphatic obstruction), uremia (bilateral ureteral obstruction)

Signs

• Exophytic, ulcerating, or endophytic (barrel-shaped) cervical lesion
• Friable cervix that bleeds on touch
• Parametrial thickening on rectal examination
• "Frozen pelvis" (bilateral parametrial involvement to pelvic sidewall) - advanced disease

---

6. DIAGNOSIS

---

7. FIGO STAGING 2018 (Current)

• Imaging (CT, MRI, PET) and pathologic findings now incorporated into staging.
• Horizontal spread no longer part of Stage IA - only depth of stromal invasion.
• Stage IB now has 3 substages (IB1, IB2, IB3).
• Stage IIIC added for pelvic (IIIC1) and para-aortic (IIIC2) lymph node metastasis; further designated by "r" (radiologic) or "p" (pathologic) - e.g., IIIC1r or IIIC1p.
• When doubt exists about stage: assign the earlier stage.
• Stage once assigned must not be changed after treatment begins.

---

8. TREATMENT SUMMARY BY STAGE

Microinvasive Disease (Stage IA)

• Desire fertility: Cone biopsy (margins and ECC must be negative)
• No fertility desire: Extrafascial (Type I) hysterectomy
• Note: <1% risk of pelvic lymph node metastasis → lymphadenectomy NOT needed

• Modified radical trachelectomy (fertility) OR modified radical hysterectomy + pelvic LND/SLN

Early Invasive Disease (IB1, IB2, IIA1)

• Radical trachelectomy + pelvic LND (if fertility desired; lesion <2 cm)
• OR Type III (Radical Wertheim's) hysterectomy + pelvic LND

• Type III radical hysterectomy + pelvic LND (for IB2, some centers)
• Concurrent cisplatin-based chemoradiation (especially IB3, IIA2 ≥4 cm)
• Not advisable to do radical hysterectomy for >4 cm lesions (high rate of requiring post-op RT)

Locally Advanced Disease (IIB-IVA)

• Standard: Concurrent cisplatin-based chemoradiation (cisplatin 40 mg/m² weekly + EBRT + brachytherapy)
• Cisplatin alone is the preferred radiosensitizer

Stage IVB / Metastatic / Recurrent

• Cisplatin + paclitaxel
• Carboplatin + paclitaxel
• Bevacizumab (VEGF inhibitor) added to doublet - improved median OS (17 vs 13.3 months; GOG 240)

• Pembrolizumab + chemotherapy ± bevacizumab - FDA approved October 2021 (KEYNOTE-826) for first-line treatment of persistent/recurrent/metastatic cervical cancer with PD-L1 CPS ≥ 1
• Median OS: 28.6 months (pembrolizumab) vs. 16.5 months (placebo)
• Updated final data (ASCO 2023): benefit persists and is seen regardless of PD-L1 status
• Pembrolizumab monotherapy - approved for second-line (post-chemotherapy) PD-L1 CPS ≥1

---

9. ADJUVANT THERAPY AFTER RADICAL HYSTERECTOMY

High-risk features (→ Adjuvant cisplatin-based chemoradiation):

• Positive pelvic lymph nodes
• Positive surgical margins
• Parametrial involvement

Intermediate-risk features (Sedlis criteria - → Adjuvant pelvic radiation):

• Combination of: large tumor size + deep stromal invasion + LVSI

---

10. RECURRENT DISEASE

• 35% of patients with invasive cervical cancer will have recurrent/persistent disease.
• Central pelvic recurrence: potentially curable with pelvic exenteration.
• Lateral pelvic/distant recurrence: palliative treatment only.

Pelvic Exenteration Types:

1. Anterior exenteration - bladder + vagina + uterus + cervix
2. Posterior exenteration - rectum + vagina + uterus + cervix
3. Total exenteration - bladder + rectum + vagina + uterus + cervix (± infralevator/supralevator)

---

11. PREVENTION

HPV Vaccination

• Gardasil-9 (9-valent) - now preferred; covers HPV 6, 11, 16, 18, 31, 33, 45, 52, 58
• 97-100% efficacy for CIN2/3 in HPV-naive recipients
• Recommended: Ages 9-12 (routine), 13-26 (catch-up), up to age 45 (shared decision-making)
• Given to both males and females

Cervical Cancer Screening

---

12. PROGNOSIS

---

13. RECENT UPDATES AND GUIDELINES (2023-2026)

---

• "HPV causes Cervical cancer - E6 kills p53, E7 kills Rb"
• IIB and above = Chemoradiation (not surgery as primary)
• IIIC = Nodes (new in 2018 FIGO)
• Pembrolizumab = first-line for metastatic if PD-L1 CPS ≥1 (KEYNOTE-826)
• LACC trial = Open > Laparoscopic for radical hysterectomy