cervical carcinoma

**Etiology and pathophysiology** - Persistent infection with high-risk HPV (16 and 18 most common; also 31, 33, 45) is the cause. - E6 promotes degradation of p53. E7 inhibits Rb, which releases E2F and drives cell-cycle progression. - Low-risk HPV types 6 and 11 cause condylomata acuminata (genital warts). They do not cause cervical cancer. - Progression: HPV infection → cervical intraepithelial neoplasia (CIN I-III) → carcinoma in situ → invasive carcinoma. This takes years, so screening can catch precursors. - The transformation zone (squamocolumnar junction) is the site of dysplasia, because metaplastic cells there are vulnerable to HPV.

**Risk factors** - Early age at first intercourse and multiple sexual partners - Smoking - Immunosuppression (HIV, transplant recipients) - Lack of screening - Long-term OCP use - High parity - Low socioeconomic status - In utero DES exposure → clear cell adenocarcinoma of the vagina or cervix

**Histologic types** - Squamous cell carcinoma: ~70-80% - Adenocarcinoma: ~20%, arises from endocervical glands. It is also HPV-related (especially HPV 18) and is harder to detect on Pap. - Adenosquamous and small cell (neuroendocrine) carcinoma: rare and aggressive. - Koilocytes (perinuclear halo with nuclear atypia, "raisinoid" nuclei) are the histologic hallmark of HPV infection.

**Clinical features** - Often asymptomatic early, which is why screening matters. - Postcoital bleeding is the classic symptom. Also intermenstrual bleeding and malodorous vaginal discharge. - Advanced disease: pelvic pain, and hydronephrosis with postrenal failure from ureteral obstruction. The cervix lies near the ureters, so this is the **most common cause of death**. - Spread is mainly local and via lymphatics (paracervical → obturator → iliac → para-aortic nodes). Cardinal ligament involvement may cause ureteral obstruction.

**Screening and prevention (USPSTF)** - Age 21-29: cytology (Pap) every 3 years. - Age 30-65: Pap every 3 years, OR high-risk HPV testing alone every 5 years, OR co-testing every 5 years. - Stop at age 65 if there is adequate prior negative screening, and after hysterectomy with cervix removal for a benign indication. - Abnormal Pap → colposcopy with biopsy. Cervical conization (LEEP or cold-knife) is used for diagnosis and treatment of high-grade lesions. In HIV, screening starts earlier and is more frequent. - HPV vaccine (9-valent Gardasil 9): routine at age 11-12 (can start at 9), with catch-up through age 26. Shared decision-making applies for ages 27-45. It is a non-infectious L1 capsid VLP vaccine and does not replace screening.

**Staging (FIGO)** - Stage I: confined to the cervix. - Stage II: extends beyond the uterus but not to the pelvic wall or lower third of the vagina. - Stage III: pelvic wall, lower vagina, hydronephrosis, or nodal involvement. - Stage IV: bladder, rectum, or distant metastasis. - Clinical staging (exam, cystoscopy, imaging) is traditional, but current FIGO also incorporates imaging and pathology findings.

**Treatment** - CIN / microinvasive disease: LEEP or conization. - Early invasive (IA2-IB1): radical hysterectomy with lymph node assessment. Simple hysterectomy is used for IA1 without lymphovascular invasion. Fertility-sparing options include radical trachelectomy. - Locally advanced (IB3-IVA): concurrent chemoradiation (cisplatin-based). - Metastatic or recurrent: chemotherapy ± bevacizumab, pembrolizumab (for PD-L1+ tumors).

**High-yield pearls** - Cervical cancer is the most common gynecologic cancer worldwide. In the US, endometrial cancer is the most common gynecologic cancer. - Most common cause of death: renal failure from ureteral obstruction. - Pap smears detect CIN and carcinoma in situ, but do not detect all adenocarcinoma. - HPV vaccination plus screening has sharply decreased incidence. - Board-style clue: young woman with postcoital bleeding and a history of abnormal Pap → colposcopy with biopsy.