Anatomy of cervix and cervical cancer workup

This ppt is on carcinoma cervix and its anatomy epidemiology and work up of carcinoma cervix

1. CERVICAL CANCER ANATOMY UPTILL WORKUP DR. KUNDANA SAI 1 ST YEAR RESIDENT DEPARTMENT OF RADIATION ONCOLOGY

2. Contents Anatomy of uterus and uterine cervix Epidemiology Risk Factors Staging Clinical Presentation Work Up Screening of CA Cervix Vaccination

3. Cervix Size: ~3 × 3 cm , roughly cylindrical Composition: Mostly fibrous tissue Divisions: Supravaginal portion: Above vaginal ring; contains endocervical canal Vaginal portion: Projects into vaginal vault Canal and Openings: External os : Central opening, bounded by anterior & posterior lips Endocervical canal: Leads to internal os , continuous with endometrial canal

4. Supravaginal Part of cervix: Related anteriorly to the bladder Post to the POD, containing coils of intestine & to rectum On each side, to ureter & to uterine artery, embedded in parametrium. Vaginal Portion of cervix projects into the anterior wall of vagina. The spaces b/w it & the vg wall are called the vaginal fornices .

5. PARAMETRIUM The parametrium is the fibro-fatty connective tissue that surrounds the uterus and cervix. It lies between the two layers of the broad ligament and extends laterally from the uterus toward the pelvic wall. Contents: Uterine vessels (artery & vein) Lymphatics (important for cervical cancer spread) Nerves Loose connective tissue

6. DIVISONS OF PARAMETRIUM Anterior Parametrium Located between bladder & cervix ( vesicouterine space) Contains vesicouterine ligament Important in radical hysterectomy – bladder mobilization Lateral Parametrium Lateral to uterus & cervix, between uterus and pelvic side wall Contains: Uterine artery & vein Lymphatics, Nerves Subdivisions (surgical): Mesometrium : Connective tissue adjacent to uterus Cardinal ligament ( Mackenrodt ): Condensed fibrous tissue giving major lateral support Clinical relevance: Major route of lymphatic spread of cervical cancer Posterior Parametrium Located between cervix/upper vagina & sacrum (rectouterine pouch area) Contains uterosacral ligaments Important in parametrial resection during Wertheim’s hysterectomy

7. Ureters are the anatomical landmark for the lateral parametrium. The proximal lateral parametrium is identified medially to the ureter, while the distal lateral parametrium is identified laterally to the ureter   Key Surgical Relevance Parametrium is resected in radical hysterectomy (Type II–III) for carcinoma cervix Extent of resection determines the radicality of surgery Parametrial involvement = important prognostic factor & part of staging (FIGO / AJCC)

8. LYMPHATIC DRAINAGE

9. Blood Supply Arterial Supply Main artery: Uterine artery Origin: Anterior division of internal iliac artery Runs medially in cardinal ligament Crosses over ureter (“water under the bridge”) Gives descending cervical branch to supply cervix Collateral supply: Vaginal artery (also from internal iliac) Anastomoses with uterine artery branches Venous Drainage Uterine venous plexus around cervix → uterine vein Drains into internal iliac vein Nerve Supply Sympathetic From hypogastric plexus Responsible for pain sensation from body & cervix during labor Parasympathetic From pelvic splanchnic nerves (S2–S4) Supply cervix & upper vagina Sensory Pain fibers travel via T10–L1 (uterine body) and S2–S4 (cervix/vagina)

10. HISTOLOGY The endocervical canal is lined by glandular or columnar epithelium exocervix , is covered by squamous epithelium Squamo -Columnar Junction is defined as the border between the stratified squamous epithelium and columnar epithelium

11. Morphogenetically , there are two SCJ. Original SCJ - seen at birth.Subsequently , with puberty, sexual activity and pregnancy there is ‘ectopy’ of the endocervical epithelium which undergoes squamous metaplasia resulting in the formation of ‘New SCJ’ which is more cranial to the original SCJ. The region between the original and new SCJ is the Transformation Zone or TZ. This concept is extremely important for understanding the pathogenesis of cervical cancer because vast majority of these cancers arise in the transformation zone.

12. Global Burden 4th most common cancer in women worldwide Incidence: ~660,000 new cases annually (GLOBOCAN 2023) Mortality: ~350,000 deaths annually Disproportionately affects low- and middle-income countries (LMICs) Leading cause of years of life lost (YLL) among women in many LMICs WHO Goal : Eliminate cervical cancer as a public health problem by 2030 90–70–90 targets: 90% of girls fully vaccinated with HPV vaccine by age 15 70% of women screened by 35 and again by 45 90% of women with pre-cancer/cancer treated Indian Burden Second most common cancer among Indian women (after breast cancer) Incidence: ~120,000 new cases per year Mortality: ~75,000 deaths annually → accounts for ~15–16% of global deaths Contributes ~20% of global cervical cancer cases Higher prevalence in rural areas due to: Lack of screening programs Limited awareness Poor access to HPV vaccination Peak incidence: 30–50 years age group (affects women in reproductive years)

13. RISK FACTORS HPV infection is associated with >90% of cervical cancer cases. Other risk factors Smoking (RR = 1.55) Immunocompromised status (Post-transplant, AIDS) History of STDs Young age at first sexual intercourse Multiple Sexual Partners Multiparity Low Socioeconomic Status DES exposure in utero (associated with clear cell adenocarcinoma of cervix/ vagin ) Family History of cervical cancer Long-term use of oral contraceptives

14. HPV – PATHOGENESIS >90% of cervical cancers are HPV-related, transmitted sexually. High-risk HPV types: Most common: HPV-16, HPV-18 Others: 31, 33, 35, 39, 45, 51, 52, 56, 58 (geographic variation exists). Causative types: HPV 16, 18, 31, 33, 45 (majority of cervical cancers). Replication site: Basal epithelial cells → episomal state initially (extrachromosomal). Progression: Viral genome integrates into host genome in most invasive cancers & some high-grade dysplasias → key step in malignant transformation Peak prevalence: Ages 25–35 years .

15. Molecular mechanisms HPV genome integrates into host cervical epithelial cell DNA. Codes for 6 early (E1–E7) & 2 late (L1–L2) proteins. Oncogenic proteins: E6 → inactivates p53 → chromosomal instability, apoptosis inhibition, telomerase activation. E7 → inactivates Rb protein → loss of cell-cycle control, uncontrolled proliferation, immortalization. Animal studies: E7 → tumor promotion, E6 → progression & malignant conversion.

16. Immune Evasion Strategies Minimizes antigen production during early/latent infection → evades immune recognition. Capsid proteins shed quickly from epithelium (low APC density). E6/E7 suppress immune-related gene expression → downregulate interferon response & antigen presentation. Natural History & Clearance 70–90% of women <25 years clear HPV in 12–24 months. Women >45 years clear infection faster. Persistent infection (esp. with high-risk HPV) → higher risk for CIN & carcinoma.

17. Histopathological Subtypes of Carcinoma Cervix Type % of Cases Variants Squamous Cell Carcinoma 70–80% Keratinizing, non-keratinizing, basaloid, verrucous, papillary Adenocarcinoma 10–25% Endocervical, mucinous, villoglandular, clear cell, serous Adenosquamous / Glassy Cell ~3–5% Mixed histology, aggressive Neuroendocrine Tumors <5% Small-cell, large-cell neuroendocrine Others (Rare) <1% Sarcomas, melanoma, lymphoma

18. Clinical Presentation of Cervical Cancer Detection in Early Stages Most common mode in developed countries: Detected during routine gynecologic exam Screening tools: Pap smear, Colposcopy + directed biopsy, HPV DNA testing These methods have high sensitivity & specificity Lesion may appear as: Exophytic growth Barrel-shaped cervix (endocervical tumor )

19. Early Symptoms Often asymptomatic (detected by screening) Abnormal vaginal bleeding: Metrorrhagia – intermenstrual bleeding Menorrhagia – heavy menstrual flow Postcoital bleeding – classic symptom Chronic blood loss → anemia → fatigue, pallor, weakness

20. Lumbosacral Pain May indicate para-aortic node (PAN) involvement Possible lumbosacral root infiltration or hydronephrosis Advanced Disease Symptoms Symptom Cause / Mechanism Foul-smelling vaginal discharge Tumor necrosis, infection Pelvic / hypogastric pain Tumor infiltration, necrosis, pelvic inflammation Flank pain / Hydronephrosis Ureteric obstruction by parametrial disease Leg pain / edema Pelvic sidewall involvement → lymphatic/venous obstruction Rectal bleeding / Obstipation Direct rectal invasion Dysuria / Hematuria Bladder invasion

21. SCREENING OF CANCER CERVIX Cervical cancer is one of the most preventable cancers , and screening is key to reducing incidence and mortality. Screening detects precancerous lesions (CIN) → allows early treatment Organized screening programs ↓ incidence & mortality by 70–80% Screening Modalities: Pap smear HPV DNA test Co-testing VIA

22. Pap Smear Test (Papanicolaou Test) Cytological examination of exfoliated cells from cervix (transformation zone) Detects precancerous lesions (CIN/SIL) & early invasive carcinoma Preparation -Explain procedure to patient & obtain consent -Ensure patient is not menstruating (best done 10–20 days after LMP) -Avoid vaginal medications/intercourse 24–48 hrs prior -Gather equipment: speculum, Ayre’s spatula, cytobrush , glass slides or liquid-based cytology vial, fixative

23. Position & Visualization Place patient in lithotomy position insert unlubricated speculum gently to visualize cervix Identify transformation zone (squamocolumnar junction) — most important sampling site

24. Collection of Sample Ectocervical Sample -Use Ayre’s spatula (broad end) -Rotate 360° around external os - Scrape entire ectocervix including transformation zone B. Endocervical Sample -Use endocervical brush / cytobrush -Insert gently into endocervical canal (no deeper than os ) -Rotate 180° to collect columnar cells

25. Preparing the Smear Conventional method: -Spread material thinly and evenly on glass slide - Fix immediately (95% ethanol or spray fixative) to prevent drying artifact - Satisfactory conventional pap smear : 8000 to 12000 squamous cells 2. Liquid-Based Cytology (LBC): just cut brush and put in Liquid 5000 squamous cells Advantages of LBC over Conventional Smear Cleaner background (less obscured by blood/mucus) Fewer unsatisfactory samples Same vial can be used for HPV DNA testing (co-testing) Better reproducibility & sensitivity

26. HPV DNA TESTING Detects high-risk HPV genotypes Uses molecular methods – PCR or Hybrid Capture 2 (HC2) assay Sample Cervical sample from transformation zone Collected with cytobrush / swab (same as Pap smear) Can also be performed on liquid-based cytology (LBC) vial Advantages Higher sensitivity (≈95%) than Pap smear Allows longer screening interval (every 5 years if negative) Detects risk before cytologic changes appear Can be combined with Pap smear (co-testing) for highest negative predictive value Limitations Lower specificity in young women (<30 yrs) due to transient infections More expensive than cytology Requires molecular lab infrastructure

27. CO-TESTING Simultaneous use of Pap smear (cytology) and HPV DNA testing on the same cervical sample Recommended for women aged ≥30 years Negative Co-test: Safely repeat after 5 years Positive Co-test: Proceed to colposcopy (especially if HPV 16/18 positive) Advantages Highest sensitivity & negative predictive value Detects cytologic abnormality + underlying HPV infection Allows longer screening interval (5 years if both negative) Early detection of HPV persistence before cytologic changes Limitations Costlier than either test alone Requires lab infrastructure (cytopathology + molecular lab) Slightly increased detection of transient HPV infections → potential over-referral

28. VIA(Visual inspection of acetowhite area) 3–5% acetic acid applied to cervix Causes acetowhite change in areas of increased nuclear activity (dysplasia/HPV infection) Lesions become white within 1 minute and then fade Procedure Place patient in lithotomy position Insert speculum & visualize cervix Apply 3–5% acetic acid with cotton swab/gauze Wait ~1 minute Observe under good light for acetowhite lesions (especially around transformation zone)

29. Advantages Low-cost, simple, immediate results No lab infrastructure needed Can be done by trained health workers Suitable for low-resource settings Allows “Screen & Treat” approach (cryotherapy/LEEP same visit) Limitations Subjective interpretation (requires training) Lower specificity than Pap smear (false positives) Not suitable for postmenopausal cervix (atrophic changes)

30. Parameter VIA (Visual Inspection with Acetic Acid) VILI (Visual Inspection with Lugol’s Iodine) Reagent Used 3–5% Acetic acid Lugol’s iodine (iodine solution) Principle Acetic acid coagulates proteins in dysplastic cells → appear acetowhite Normal glycogen-rich squamous epithelium takes up iodine (brown/black). Dysplastic areas lack glycogen → remain unstained (yellow) Procedure Apply acetic acid, wait 1 min, look for acetowhite lesions near SCJ Apply iodine, observe iodine uptake pattern Positive Test Dense, well-defined acetowhite area Yellow/mustard yellow area (no iodine uptake) Advantages Simple, low-cost, immediate result; widely validated Higher contrast between normal & abnormal areas (better visibility in some cases) Limitations Can give false positives (metaplasia, inflammation) Not suitable in iodine allergy or pregnancy; needs extra step after VIA

31. COLPOSCOPY Colposcopy = Examination of cervix, vagina, and vulva using a colposcope (binocular microscope with light source & magnification) Allows magnified visualization of cervical epithelium to detect precancerous & cancerous lesions Indications Abnormal Pap smear (ASC-US with HPV+, LSIL, HSIL) Suspicious cervix on visual inspection (VIA/VILI positive) Persistent unexplained postcoital bleeding Follow-up after treatment for CIN

32. Procedure Place patient in lithotomy position, insert speculum Examine cervix under white light Apply 3–5% acetic acid → observe acetowhite areas Apply Lugol’s iodine (Schiller’s test) → abnormal areas remain unstained Identify transformation zone & SCJ Targeted biopsy from abnormal areas

33. Colposcopic Findings Normal: Pink epithelium, smooth SCJ Abnormal (Suggestive of CIN): Acetowhite epithelium Punctation (dilated capillaries) Mosaic pattern Atypical vessels (irregular, coarse) → suggest invasive cancer Advantages Guides directed biopsy (improves diagnostic accuracy) Can be done as OPD procedure Painless, quick, reproducible Limitations Requires trained colposcopist Subjective interpretation Limited availability in rural areas

34. Management Based on Cytology (Pap Smear) Report Negative for Intraepithelial Lesion or Malignancy (NILM) Meaning: Normal smear Action: Routine screening 21–29 yrs → Repeat Pap every 3 yrs 30–65 yrs → Pap every 3 yrs (or HPV test every 5 yrs / co-testing every 5 yrs) ASC-US (Atypical Squamous Cells – Undetermined Significance) Meaning: Mild atypia, not enough for LSIL Action: Age ≥25 yrs: Reflex HPV testing preferred HPV negative: Routine screening (repeat after 3 yrs) HPV positive: Colposcopy + directed biopsy Age 21–24 yrs: Repeat cytology after 12 months (no HPV test)

35. LSIL (Low-grade Squamous Intraepithelial Lesion) Meaning: Suggests HPV infection / CIN1 Action: Age ≥25 yrs: Colposcopy (regardless of HPV result) Age 21–24 yrs: Repeat cytology after 12 months ASC-H (Atypical Squamous Cells – cannot exclude HSIL) Meaning: Changes suspicious for HSIL Action: Immediate colposcopy ± biopsy HSIL (High-grade SIL) Meaning: Suggestive of CIN2 / CIN3 Action: Immediate colposcopy + biopsy If CIN2+ confirmed → excisional procedure (LEEP / cone biopsy)

36. AGC (Atypical Glandular Cells) / AIS (Adenocarcinoma in situ) Meaning: Glandular abnormality (precursor for adenocarcinoma) Action: Colposcopy + Endocervical curettage (ECC) Endometrial sampling (if >35 yrs or risk factors present) Malignant Cells (SCC / Adenocarcinoma) Meaning: Invasive cancer suspected Action: Colposcopy + Biopsy Staging work-up & definitive management (RT/Surgery)

37. PRIMARY PREVENTION OF CERVICAL CANCER Main strategy: HPV vaccination (targets oncogenic HPV types) Vaccine HPV Types Covered Special Features Bivalent ( Cervarix ) 16, 18 High protection against oncogenic types Quadrivalent (Gardasil) 6, 11, 16, 18 Adds protection against genital warts Nonavalent (Gardasil-9) 6, 11, 16, 18, 31, 33, 45, 52, 58 Broader coverage – 90% of HPV-related cancers

38. Recommended Age & Schedule Routine vaccination: Age 9–14 years (girls & boys) Catch-up: Up to 26 years Dose Schedule: 9–14 years: 2 doses (0, 6–12 months) ≥15 years: 3 doses (0, 1–2, 6 months) Efficacy >95% reduction in CIN 1/2/3 due to vaccine-specific HPV types in HPV-naïve women Protection lasts ≥5–10 years, long-term data for Gardasil-9 promising Early evidence: even 1 dose may offer protection against HPV 16 & 18

39. Staging Workup for Carcinoma Cervix 1 . Clinical Evaluation Detailed history Symptoms: bleeding (intermenstrual, postcoital, postmenopausal), discharge, pain, urinary/bowel complaints. Risk factors: parity, sexual history, prior Pap smears, HPV exposure, immunosuppression. General examination Performance status, comorbidities. Gynecologic examination Speculum exam: visualize tumor , site, size, ulceroproliferative / exophytic. Bimanual pelvic exam: check for parametrial involvement, vaginal extension. Rectovaginal exam: assess uterosacral ligaments, rectal involvement, pelvic sidewall fixation.

40. 2. Laboratory Workup Routine blood tests: CBC, RFT, LFT (to assess fitness for RT/chemotherapy). Serology: HIV, HBsAg, HCV Pregnancy test: in reproductive-age women. 3. Pathology Punch biopsy / wedge biopsy from the lesion → histological diagnosis. Endocervical curettage (ECC): if transformation zone not fully visualized. Cone biopsy: if microinvasive disease suspected (IA).

41. 4. Imaging Workup Modality Use MRI (preferred) Best for local staging → tumor size, parametrial invasion, bladder/rectal involvement CT Scan Nodal status & distant spread, but limited sensitivity for small metastases PET/CT Most sensitive & specific for nodal & distant metastasis Ultrasound / X-ray Used in low-resource settings

42. MRI T1-Weighted Imaging (T1WI) Role: Baseline anatomy Detecting lymph nodes (enlargement) Detecting hemorrhage (hyperintense on T1) Tumor often isointense to normal cervix → not ideal for tumor delineation Post-Contrast T1 (Gadolinium-Enhanced) Use: Helpful in differentiating tumor vs. post-biopsy inflammation Useful in equivocal cases Not routinely required for all cases T2-Weighted Imaging (T2WI) Most important sequence for local staging Best for: Assessing tumor size & extent Parametrial invasion (loss of low-signal fat plane) Involvement of adjacent structures (uterus, vagina, bladder, rectum) Appearance: Tumor = intermediate-to-high signal intensity Normal fibrocervical stroma = low signal intensity → acts as a dark rim Helps differentiate tumor vs. stroma

43. PET/CT A lymph node is considered positive for metastasis when it is within the anatomic nodal drainage pathway for the primary tumor and demonstrates tracer uptake greater than that of a clearly a normal node elsewhere on the scan Detects nodal and distant metastasis (pelvic, para-aortic, supraclavicular) More sensitive & specific than CT/MRI for nodal staging Diagnostic performance Parameter PET/CT Sensitivity for PAN nodes ~90–92% Specificity ~95–97% NPV ~90–93% (negative PET strongly predicts node-negative status)

44. Limitations False positives (inflammation, infection) False negatives in micrometastasis (<5 mm) Costly and not universally available Requires patient preparation (fasting, good glycemic control)

45. FIGO Staging of Cancer of the Cervix Uteri (2018)

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