Carcinoma Cervix

Carcinoma of the cervix is the commonest gynaecological malignancy in India and the second commonest cancer in Indian women. It is almost entirely caused by persistent high-risk HPV infection, making it the only common cancer that is both screenable and vaccine-preventable. For NEET PG, the perennial hot zones are HPV aetiology, the Bethesda/Pap terminology, the FIGO 2018 staging revision, and the anatomical extent of Wertheim's radical hysterectomy.

Epidemiology & risk factors

Worldwide, cervical cancer is the 4th commonest cancer in women; in India it accounts for a disproportionately large share owing to absent organised screening. Peak incidence is at 45–55 years, with a smaller second peak.

High-yield: Persistent infection with high-risk HPV (especially types 16 and 18) is a necessary cause — HPV DNA is detectable in ~99.7% of squamous cancers. HPV 16 + 18 together cause ~70% of cervical cancers.

Key risk factors:

Factor	Mechanism / note
Persistent high-risk HPV (16, 18, 31, 33, 45)	E6 inactivates p53, E7 inactivates Rb → loss of cell-cycle control
Early age at first intercourse, multiple partners	Greater HPV exposure
Multiparity, early first pregnancy	Cervical trauma, hormonal
Smoking	Cofactor — squamous cancers
Immunosuppression (HIV)	Reduced HPV clearance; AIDS-defining
Long-term OCP use (>5 yr)	Modest risk
Low socioeconomic status, poor screening	Late presentation

High-yield: HPV oncoproteins — remember "E6 eats p53, E7 hits Rb." HPV 16 → squamous cell carcinoma, HPV 18 → adenocarcinoma (and more aggressive).

Pathology & natural history

The transformation occurs at the squamocolumnar junction (transformation zone) — the site of active squamous metaplasia and the target of screening and colposcopy.

Histological types:

• Squamous cell carcinoma — ~70–80% (most common).
• Adenocarcinoma — ~20% (rising proportion; arises from endocervical glands; HPV 18; harder to detect on Pap as it is endocervical).
• Adenosquamous, small-cell neuroendocrine (very aggressive), clear cell (DES exposure), rare types.

Natural progression (flow):

HPV infection → CIN 1 (LSIL) → CIN 2/3 (HSIL) → carcinoma-in-situ → microinvasive → invasive carcinoma.

This sequence typically spans 10–20 years, providing a long screen-detectable preclinical phase. Many CIN 1 lesions regress spontaneously; CIN 3 carries the highest risk of progression.

CIN ↔ Bethesda terminology

Older (Dysplasia)	CIN	Bethesda (cytology)
Mild dysplasia	CIN 1	LSIL
Moderate dysplasia	CIN 2	HSIL
Severe dysplasia / CIS	CIN 3	HSIL

ASC-US = atypical squamous cells of undetermined significance; ASC-H = cannot exclude HSIL; AGC = atypical glandular cells (worrying — needs endocervical + endometrial sampling).

Clinical features

Early disease (CIN, microinvasion) is asymptomatic — hence screening. Symptomatic presentation indicates invasive disease.

• Postcoital bleeding — classic earliest symptom.
• Intermenstrual / irregular bleeding, postmenopausal bleeding.
• Foul-smelling, blood-stained vaginal discharge.
• Advanced: pelvic/back pain, leg oedema (lymphatic/venous obstruction), sciatica, haematuria/rectal bleeding (fistulae), uraemia from bilateral ureteric obstruction.

High-yield: The commonest cause of death in carcinoma cervix is uraemia due to bilateral ureteric obstruction (renal failure), not metastasis to distant organs.

On speculum: a friable, bleeding exophytic growth or an indurated ulcer / barrel-shaped cervix (endophytic).

Spread

• Direct (most important): to vagina, parametrium → pelvic side wall, bladder, rectum.
• Lymphatic: parametrial → obturator → internal/external iliac → common iliac → para-aortic. Lymphatic spread is orderly and stepwise.
• Haematogenous (late): lung, liver, bone.

High-yield: Cervical cancer spreads predominantly by direct extension and lymphatics; blood spread is late. The ureter runs through the parametrium beneath the uterine artery ("water under the bridge") — explaining ureteric obstruction and the surgical risk during radical hysterectomy.

Screening

High-yield: Begin screening at age 21 (or per current ICMR/WHO guidance based on sexual activity). Pap smear every 3 years (21–29 yr); co-testing (Pap + HPV) every 5 years or HPV testing alone every 5 years (30–65 yr). WHO now favours HPV DNA as the primary screening test.

Screening modalities:

Test	Note
Pap smear (cytology)	Conventional or liquid-based (LBC); samples transformation zone
HPV DNA testing	Most sensitive; primary test per WHO
VIA (Visual Inspection with Acetic acid)	Acetowhite areas; mainstay in low-resource India ("see-and-treat")
VILI (Lugol's iodine)	Schiller test — normal squamous epithelium stains brown; lesions don't stain

WHO 90-70-90 elimination target: 90% HPV-vaccinated by 15, 70% screened twice (by 35 and 45), 90% of those with disease treated.

Diagnosis & investigation of choice

Screening detects abnormality; diagnosis is by biopsy, never by Pap alone.

Diagnostic flow:

Abnormal Pap/HPV → Colposcopy → Directed punch biopsy (± endocervical curettage) → if microinvasion suspected → Cone biopsy (LEEP/cold-knife) → Histological confirmation → FIGO staging.

• Colposcopy after applying 3–5% acetic acid: look for acetowhite epithelium, punctation, mosaicism, atypical vessels. Abnormal vessels suggest invasion.
• Cone biopsy / LEEP is needed to assess depth of invasion and lateral spread when microinvasion is suspected or the lesion extends into the canal.

High-yield: The investigation of choice for definitive diagnosis is biopsy (colposcopy-directed punch biopsy). Cone biopsy is required to diagnose/measure microinvasion (Stage IA).

Staging work-up may include cystoscopy, sigmoidoscopy, IVP/CT urogram, chest X-ray; MRI best assesses parametrial/local extent; PET-CT for nodal/distant disease.

FIGO 2018 staging (clinical + imaging + pathology allowed)

A landmark change: FIGO 2018 permits imaging (MRI/CT/PET) and pathological findings to be incorporated, and lymph node status now affects stage.

Stage	Definition
IA1	Stromal invasion ≤3 mm depth (microinvasive)
IA2	Invasion >3 mm and ≤5 mm depth
IB1	Invasive, ≤5 mm depth excluded; lesion ≤2 cm, depth >5 mm
IB2	Lesion >2 cm and ≤4 cm
IB3	Lesion >4 cm (confined to cervix)
II	Beyond uterus, not to pelvic wall / lower 1/3 vagina
IIA	Upper 2/3 vagina, no parametrial involvement (IIA1 ≤4 cm, IIA2 >4 cm)
IIB	Parametrial involvement, not to pelvic side wall
III	Lower 1/3 vagina / pelvic side wall / hydronephrosis / nodes
IIIA	Lower 1/3 vagina, no pelvic wall
IIIB	Pelvic side wall and/or hydronephrosis / non-functioning kidney
IIIC	Pelvic (IIIC1) or para-aortic (IIIC2) lymph node involvement — NEW in 2018
IVA	Bladder / rectal mucosa (biopsy-proven)
IVB	Distant metastasis

High-yield: The two most-tested 2018 changes — (1) Stage IA defined by depth of invasion only (≤5 mm); horizontal width removed, and (2) Stage IIIC added for nodal disease (IIIC1 pelvic, IIIC2 para-aortic). Earlier, staging was purely clinical; now imaging/pathology are allowed.

High-yield: Bullous oedema of the bladder does NOT qualify as Stage IVA — there must be biopsy-proven mucosal involvement.

Management — stage-wise

Principle

• Early disease (≤ IB2 / IIA1): surgery or radiotherapy give equal results → surgery preferred in younger women (preserves ovaries, vaginal function).
• Locally advanced (IB3, IIB and above): concurrent chemoradiation is the standard of care.

Stage	Treatment of choice
CIN / IA1 (no LVSI, fertility desired)	LEEP / cone biopsy (fertility-sparing) or simple hysterectomy
IA1 (family complete)	Extrafascial (simple/Type I) hysterectomy
IA2	Modified radical (Type II) hysterectomy + pelvic lymphadenectomy
IB1–IB2, IIA1	Radical (Wertheim's, Type III) hysterectomy + pelvic lymphadenectomy
IB3, IIA2, IIB–IVA	Concurrent chemoradiation (cisplatin) + brachytherapy
Fertility desire, ≤2 cm	Radical trachelectomy (Dargent's) + lymphadenectomy
IVB / recurrent	Palliative chemo ± bevacizumab; pembrolizumab

High-yield: Drug of choice for chemoradiation = cisplatin (radiosensitiser), given weekly with external beam radiotherapy, followed by intracavitary brachytherapy. Concurrent chemoradiation is superior to radiotherapy alone for locally advanced disease.

Wertheim's radical hysterectomy (Type III) — what it removes

High-yield: Wertheim's operation removes the uterus, cervix, upper one-third (1–2 cm cuff) of vagina, both parametria up to the pelvic side wall, and uterosacral ligaments, with pelvic lymphadenectomy. Ovaries can be conserved in young women (cervical SCC rarely spreads to ovaries). It is essentially uterus + parametrium + vaginal cuff + nodes.

Piver–Rutledge classification of extended hysterectomy:

Type	Extent
Type I	Extrafascial (simple) hysterectomy
Type II	Modified radical — removes medial ½ parametrium, ureter unroofed
Type III	Classic Wertheim — parametrium removed to pelvic wall; uterosacrals divided near sacrum
Type IV	Extended radical — periureteric tissue, superior vesical artery sacrificed
Type V	Partial exenteration — resects ureter/bladder

The major intra-operative hazard is ureteric injury (the ureter is dissected off the parametrium). The commonest long-term complication is bladder dysfunction from autonomic nerve damage — hence nerve-sparing radical hysterectomy is now favoured.

Complications

• Disease: ureteric obstruction → hydronephrosis → uraemia (commonest cause of death); vesicovaginal / rectovaginal fistula; haemorrhage; pelvic side-wall pain.
• Surgery: ureteric/bladder injury, bladder atony / voiding dysfunction, lymphocyst, lymphoedema, sexual dysfunction.
• Radiotherapy: radiation cystitis, proctitis, vaginal stenosis/dryness, ovarian failure, late radiation enteritis/fistula.

Prognosis & follow-up

5-year survival depends mainly on stage and lymph node status (the single most important prognostic factor). Roughly: Stage I ~85–90%, II ~65%, III ~40%, IV <20%. Follow-up is clinical, 3-monthly initially.

Prevention — HPV vaccine

High-yield: HPV vaccines — bivalent (16,18 — Cervarix), quadrivalent (6,11,16,18 — Gardasil), nonavalent (Gardasil-9, +31/33/45/52/58). Best given before sexual debut, ideally age 9–14 years. WHO now endorses a single-dose schedule for 9–14 years; two doses also used. India's indigenous CERVAVAC is quadrivalent.

Mnemonic for quadrivalent coverage: "6, 11 cause warts; 16, 18 cause cancer."

Key differentials

Differential	Distinguishing feature
Cervical ectropion / erosion	Benign, no atypical vessels on colposcopy, normal biopsy
Cervical polyp	Benign pedunculated; histology benign
Cervical tuberculosis	Granulomas on biopsy; rare
Endometrial carcinoma extending to cervix	Postmenopausal bleeding, endometrial origin on biopsy
Vaginal carcinoma (upper)	Origin from vaginal wall; staged separately
Cervicitis (chlamydia/HSV)	Inflammatory; resolves with treatment

Recently asked / exam angle

• FIGO 2018 changes: "What is new in FIGO 2018 staging of cervical cancer?" — answer: imaging/pathology allowed, Stage IA by depth only, IIIC for nodes (IIIC1 pelvic, IIIC2 para-aortic).
• Wertheim's hysterectomy — structures removed; ovaries conserved; ureter at risk.
• Pap/Bethesda terminology — match LSIL = CIN 1, HSIL = CIN 2/3.
• HPV type associations — 16 → squamous, 18 → adenocarcinoma; E6/p53, E7/Rb.
• Screening intervals and shift to HPV DNA primary screening / WHO 90-70-90.
• Investigation of choice — colposcopy-directed biopsy (diagnosis); cone biopsy for microinvasion.
• Commonest cause of death — uraemia/renal failure.
• Treatment of locally advanced disease — concurrent cisplatin chemoradiation + brachytherapy.
• Schiller test and VIA in resource-limited settings.
• Radical trachelectomy for fertility preservation in early small tumours.

Rapid revision

• HPV 16 + 18 → ~70% of cervical cancers; 16 = squamous, 18 = adenocarcinoma.
• E6 → p53, E7 → Rb inactivation drives carcinogenesis.
• Cancer arises at the transformation zone (squamocolumnar junction).
• Earliest symptom = postcoital bleeding; classic late finding = leg oedema/hydronephrosis.
• Commonest cause of death = uraemia from bilateral ureteric obstruction.
• LSIL = CIN 1; HSIL = CIN 2/3; ASC-H needs colposcopy.
• Diagnosis = colposcopy-directed biopsy; cone/LEEP for microinvasion (Stage IA).
• FIGO 2018: Stage IA by depth ≤5 mm only; IIIC = nodal (1 pelvic, 2 para-aortic).
• Wertheim's (Type III) = uterus + parametrium to pelvic wall + uterosacrals + upper vaginal cuff + pelvic nodes; ovaries spared in young women.
• Cisplatin = radiosensitiser of choice; concurrent chemoradiation + brachytherapy for locally advanced disease.
• Lymph node status is the most important prognostic factor.
• HPV vaccine before sexual debut (9–14 yr); WHO allows single dose; India's CERVAVAC is quadrivalent.
• VIA / Schiller (Lugol's iodine) test for low-resource screening; WHO favours HPV DNA primary screening.
• Bullous bladder oedema is NOT Stage IVA — needs biopsy-proven mucosal invasion.