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Summary Table

Feature	Detail
Risk Factors	Persistent high-risk HPV infection (types 16, 18), early onset of sexual activity, multiple sexual partners, immunosuppression (HIV, transplant recipients), smoking, prolonged oral contraceptive use (>5 years), high parity, co-infection with other STIs (Chlamydia, HSV-2), lack of screening
Etiology	Persistent infection with oncogenic HPV strains; HPV 16 (squamous cell carcinoma) and HPV 18 (adenocarcinoma); viral oncoproteins E6 inactivates p53, E7 inactivates Rb
Patient Presentation	Abnormal uterine bleeding (postcoital bleeding is the hallmark), foul-smelling vaginal discharge, pelvic pain; advanced disease may present with flank pain (ureteral obstruction), leg edema, or rectal bleeding
Classic Physical Exam	Visible cervical mass or ulceration on speculum exam, friable cervix that bleeds on contact, barrel-shaped cervix (endocervical tumor growth)
Key Diagnostic Results	Abnormal Pap smear (screening), positive high-risk HPV test, cervical biopsy via colposcopy (confirmatory), MRI pelvis for staging
Management	Precancerous lesions: excision (LEEP/cone biopsy). Early-stage (IA1): cone biopsy or simple hysterectomy. Stage IA2-IB1: radical hysterectomy + pelvic lymphadenectomy. Stage IB2 and above: concurrent chemoradiation (cisplatin-based)
Keywords	Postcoital bleeding, koilocytes, high-risk HPV, E6/E7 oncoproteins, LEEP, concurrent chemoradiation, Pap smear, transformation zone

1. Pathophysiology

Cervical cancer arises from the transformation zone of the cervix, where columnar epithelium of the endocervix meets the squamous epithelium of the ectocervix. This junction is the most metabolically active area of the cervix and is uniquely vulnerable to HPV infection because of its high rate of squamous metaplasia.

Persistent infection with high-risk HPV (primarily types 16 and 18) is the necessary precondition for nearly all cervical cancers. HPV gains access to the basal epithelial cells through microabrasions. Once integrated into the host genome, two viral oncoproteins drive malignant transformation. E6 binds and degrades p53 through the ubiquitin-proteasome pathway, eliminating the cell's ability to undergo apoptosis and DNA damage repair. E7 binds and inactivates the retinoblastoma protein (Rb), releasing E2F transcription factors and driving uncontrolled cell cycle progression past the G1/S checkpoint. The combined loss of both tumor suppressors results in genomic instability, accumulation of mutations, and progression from CIN I to CIN II to CIN III (carcinoma in situ) and eventually invasive carcinoma. This progression typically takes 10 to 20 years, which is why screening is so effective.

The reason patients present with postcoital bleeding is that the neoplastic tissue in the transformation zone is friable and highly vascularized. Mechanical contact during intercourse disrupts these fragile vessels. As the tumor grows, it may invade the parametria, compress the ureters (causing hydronephrosis and flank pain), invade the bladder or rectum, or obstruct lymphatic drainage (causing lower extremity edema). Foul-smelling discharge occurs from tumor necrosis and secondary bacterial infection of the necrotic tissue.

2. Classification and Clinical Manifestation

Histological Classification

Type	Frequency	HPV Association	Notes
Squamous Cell Carcinoma	~70-80%	HPV 16 (most common)	Arises from ectocervical squamous epithelium; preceded by squamous intraepithelial lesions
Adenocarcinoma	~20-25%	HPV 18 (most common)	Arises from endocervical glandular epithelium; may be missed by Pap smear because lesions are higher in the canal
Adenosquamous Carcinoma	~3-5%	HPV 16, 18	Mixed histology; tends to have worse prognosis than pure subtypes
Small Cell / Neuroendocrine	Rare	HPV 18	Aggressive behavior; treated similarly to small cell lung cancer

Cervical Intraepithelial Neoplasia (CIN) and Bethesda Classification

CIN Grade	Bethesda Equivalent	Dysplasia Depth	Behavior
CIN I	Low-grade Squamous Intraepithelial Lesion (LSIL)	Dysplasia limited to the lower 1/3 of epithelium	Majority regress spontaneously (60-80%); observation is acceptable in young patients
CIN II	High-grade Squamous Intraepithelial Lesion (HSIL)	Dysplasia extends to the lower 2/3	Intermediate risk of progression; treatment recommended in most patients
CIN III / Carcinoma in Situ	HSIL	Full-thickness dysplasia but no basement membrane invasion	High risk of progression to invasive cancer; treatment is mandatory

FIGO Staging (Clinical Staging)

Stage	Description	Key Clinical Implication
I	Confined to the cervix	IA1: stromal invasion ≤3 mm depth. IA2: invasion 3-5 mm. IB: clinically visible or >5 mm invasion
II	Extends beyond the cervix but not to the pelvic sidewall or lower 1/3 of vagina	IIA: no parametrial involvement. IIB: parametrial involvement (marks the shift from surgical to chemoradiation management)
III	Extends to the pelvic sidewall, lower 1/3 of vagina, or causes hydronephrosis	IIIB: ureteral obstruction or hydronephrosis regardless of tumor size
IV	Invasion of bladder/rectal mucosa (IVA) or distant metastases (IVB)	IVB: lung, liver, bone metastases

A critical exam concept: cervical cancer is staged clinically, not surgically. This is because the disease is most prevalent in low-resource settings where surgical staging is not feasible. The staging relies on physical examination, colposcopy, biopsy, and basic imaging (chest X-ray, IVP, cystoscopy, proctoscopy). However, in practice, MRI is now the preferred imaging modality for assessing tumor size, parametrial invasion, and nodal involvement.

3. Diagnostic Workup

Test	Role	Key Findings
Pap Smear (Cervical Cytology)	Screening test	Atypical cells: ASC-US, LSIL, HSIL, AGC
HPV Co-testing	Screening (combined with Pap)	Detects high-risk HPV DNA (types 16, 18, and others)
Colposcopy + Biopsy	Best confirmatory test	Acetowhite epithelium, punctation, mosaicism; biopsy confirms CIN grade or invasion
Endocervical Curettage (ECC)	Adjunct during colposcopy	Samples the endocervical canal when the transformation zone is not fully visualized
Cone Biopsy (LEEP or Cold Knife)	Diagnostic and therapeutic	Used when ECC is positive, colposcopy is inadequate, or cytology-histology discordance exists
MRI Pelvis	Staging (local extent)	Best modality for parametrial invasion, tumor volume, and nodal assessment
PET-CT	Staging (distant disease)	Detects distant metastases and involved lymph nodes in advanced disease
Cystoscopy / Proctoscopy	Staging	Evaluates bladder or rectal mucosal invasion (Stage IVA)

Screening Approach

The entry point into cervical cancer diagnosis is almost always through screening, not symptoms. Current guidelines recommend:

For patients aged 21 to 29, Pap smear alone every 3 years is the standard. HPV testing is not recommended in this age group because transient HPV infections are extremely common and would generate unnecessary follow-up.

For patients aged 30 to 65, Pap smear + HPV co-testing every 5 years is preferred. Alternatively, Pap smear alone every 3 years or primary HPV testing alone every 5 years are acceptable. Screening can be discontinued after age 65 if prior results have been consistently normal.

Triage of Abnormal Results

When the Pap smear returns as ASC-US (atypical squamous cells of undetermined significance), the next step is reflex HPV testing. If HPV-positive, proceed to colposcopy. If HPV-negative, return to routine screening.

When cytology shows LSIL, proceed directly to colposcopy (HPV testing is not needed because LSIL has a high rate of HPV positivity).

When cytology shows HSIL or AGC (atypical glandular cells), proceed directly to colposcopy with endocervical curettage. HSIL warrants immediate evaluation because the risk of CIN II or worse is approximately 50-70%.

Diagnosis Confirmation

Colposcopy with directed biopsy is the gold standard for diagnosing cervical dysplasia and early invasive cancer. The colposcopist applies acetic acid (3-5%) to the cervix; dysplastic areas turn white (acetowhite changes) because of increased nuclear density. Lugol iodine (Schiller test) can also be applied: normal glycogen-rich squamous epithelium stains dark brown, while dysplastic areas remain unstained (Schiller-positive).

If the entire transformation zone cannot be visualized (unsatisfactory colposcopy), or if the ECC returns positive, a cone biopsy (excisional procedure) is required to rule out invasive disease.

4. Management and Treatment

Stage / Condition	Treatment	Key Details
CIN I (LSIL)	Observation with repeat co-testing at 12 months	Most regress; treat only if persistent >2 years
CIN II-III (HSIL)	LEEP (Loop Electrosurgical Excision Procedure) or cold knife conization	LEEP preferred for ectocervical lesions; cold knife cone for endocervical extension or suspected adenocarcinoma in situ
Stage IA1 (no LVSI)	Cone biopsy with negative margins OR simple (extrafascial) hysterectomy	Cone biopsy alone is acceptable for fertility preservation
Stage IA1 with LVSI, IA2	Modified radical hysterectomy + pelvic lymphadenectomy	Sentinel lymph node mapping increasingly used
Stage IB1-IIA	Radical hysterectomy (Wertheim) + bilateral pelvic lymphadenectomy OR primary chemoradiation	Both options have equivalent survival; choice depends on patient factors
Stage IIB-IVA	Concurrent chemoradiation: cisplatin 40 mg/m² IV weekly + external beam radiation + brachytherapy	This is the standard of care; surgery is not primary treatment at this stage
Stage IVB (metastatic)	Systemic therapy: cisplatin + paclitaxel + bevacizumab; immunotherapy with pembrolizumab for PD-L1 positive or MSI-high tumors	Palliative intent; radiation for symptom control
Recurrent disease	Pelvic exenteration (if central recurrence after radiation) or systemic chemotherapy	Exenteration is a curative option only for isolated central pelvic recurrence

Precancerous Lesions (CIN II-III) The treatment of choice is LEEP, which uses a thin wire loop with electrical current to excise the transformation zone. It serves as both diagnostic (provides a specimen for histologic evaluation of margins) and therapeutic. The procedure is performed in an outpatient setting under local anesthesia. Cold knife conization is reserved for situations where a larger or deeper specimen is needed, such as suspected adenocarcinoma in situ (AIS) or when colposcopy is inadequate. After excision, patients are followed with co-testing at 12 and 24 months.

Early Invasive Cancer (Stage IA1 to IIA) For microinvasive disease (Stage IA1 without lymphovascular space invasion), cone biopsy with clear margins is sufficient and allows fertility preservation. If childbearing is complete, simple hysterectomy is an alternative.

For Stage IA2 through IB1, radical hysterectomy (removal of the uterus, parametria, upper vagina, and uterosacral ligaments) with bilateral pelvic lymph node dissection is the standard surgical approach. Ovaries can be preserved in premenopausal patients with squamous cell carcinoma because ovarian metastasis is rare.

For patients who desire fertility preservation with tumors ≤2 cm, radical trachelectomy (removal of the cervix with preservation of the uterine corpus) with lymphadenectomy is an option.

Locally Advanced Cancer (Stage IIB and Beyond) Once the tumor has invaded the parametrium (Stage IIB), surgery is no longer the primary treatment. The standard of care is concurrent chemoradiation: cisplatin 40 mg/m² IV administered weekly during external beam radiation therapy (EBRT), followed by intracavitary brachytherapy. The total treatment duration should not exceed 8 weeks, as prolonged treatment time is associated with worse outcomes. Cisplatin acts as a radiosensitizer, improving the efficacy of radiation.

Adjuvant Therapy After Surgery If pathology after radical hysterectomy reveals high-risk features (positive margins, parametrial invasion, or positive lymph nodes), the patient should receive adjuvant chemoradiation (Sedlis criteria for intermediate risk; Peters criteria for high risk). Intermediate-risk factors (large tumor size, deep stromal invasion, LVSI) may warrant adjuvant radiation alone.

5. Differential Diagnosis and Distractors

Differential Diagnosis	Why It Is Similar	Key Discriminator
Cervical Polyp	Can cause postcoital bleeding and a visible cervical lesion	Polyps are smooth, pedunculated, and non-friable; biopsy shows benign endocervical glands without dysplasia
Cervicitis (Chlamydia / Gonorrhea)	Mucopurulent discharge, friable cervix, postcoital bleeding	Patient is younger, sexually active with a new partner; cervical cultures / NAAT positive for STI; no mass on exam
Endometrial Cancer	Abnormal uterine bleeding, may have abnormal Pap (AGC)	Typically postmenopausal, obese, with unopposed estrogen exposure; endometrial biopsy confirms the source; cervix appears normal
Vaginal Cancer	Vaginal bleeding, visible mass in the vaginal canal	Mass originates from the vaginal wall, not the cervix; much rarer; often in older women with prior radiation exposure or DES exposure
Threatened Abortion	Vaginal bleeding in a reproductive-age woman	Positive pregnancy test, open cervical os, products of conception visible; always rule out pregnancy before invasive workup
Cervical Ectropion	Red, friable-appearing cervix, may cause postcoital spotting	Common in young women on oral contraceptives or during pregnancy; columnar epithelium is visible on ectocervix but appears smooth and non-ulcerated; biopsy is normal
Nabothian Cyst	Visible cervical lesion	Smooth, round, mucus-filled cyst; asymptomatic; no bleeding or discharge

6. Traps and High-Yield Pearls

The most common way students lose points on cervical cancer questions is by confusing screening intervals and triage algorithms. Test-writers frequently present an ASC-US Pap result and ask for the next step. The answer is reflex HPV testing, not immediate colposcopy. Conversely, when the Pap shows HSIL, the next step is colposcopy, and you should not waste time with HPV testing because the pre-test probability of significant dysplasia is already high enough to warrant direct evaluation.

Another classic trap involves the management threshold at Stage IIB. Students often select radical hysterectomy for locally advanced disease, but once parametrial invasion is present, the correct answer shifts to concurrent chemoradiation. Remember: parametrial invasion = no surgery as primary treatment.

A frequently tested pearl is the distinction between HPV 16 and HPV 18. HPV 16 is the most common cause of cervical cancer overall and is strongly linked to squamous cell carcinoma. HPV 18 is more closely associated with adenocarcinoma. This matters because adenocarcinoma arises higher in the endocervical canal and may be missed by standard Pap smear, which is why HPV co-testing improves detection.

Students also confuse CIN I with LSIL as an indication for treatment. CIN I has a high rate of spontaneous regression, and the correct answer is surveillance, not LEEP. Treatment is reserved for CIN II and above. The exception is persistent CIN I lasting more than 2 years.

Regarding the HPV vaccine, it covers HPV types 6, 11 (responsible for genital warts), 16, and 18 (the 9-valent vaccine adds types 31, 33, 45, 52, and 58). Vaccination does not eliminate the need for screening because it does not cover all oncogenic HPV strains.

Finally, remember that cervical cancer is clinically staged, unlike endometrial and ovarian cancer, which are surgically staged. This distinction is a favorite question format: presenting a patient with cervical cancer and asking whether operative findings change the stage. They do not.

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